Stimulation for treating and diagnosing conditions

ABSTRACT

A method is provided for facilitating a diagnosis of a condition of a subject, including applying a current to a site of the subject selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, and a neural tract originating in or leading to the SPG, and configuring the current to increase conductance of molecules from brain tissue of the subject through a blood brain barrier (BBB) of the subject into a systemic blood circulation of the subject. The method also includes sensing a quantity of the molecules from a site outside of the brain of the subject, following initiation of application of the current.

CROSS-REFERENCES TO RELATED AND APPLICATIONS

The present application:

-   -   (a) is a continuation-in-part of (i) International Patent        Application PCT/IL03/00338, filed Apr. 25, 2003, (ii)        International Patent Application PCT/IL03/00508, filed Jun. 13,        2003, and (iii) U.S. patent application Ser. No. 10/783,113,        filed Feb. 20, 2004, and    -   (b) claims priority from U.S. Provisional Patent Application        60/506,165 to Shalev, filed Sep. 26, 2003.

The '338 application claims priority from (a) U.S. Provisional PatentApplication 60/376,048 to Shalev, filed Apr. 25, 2002, and (b) U.S.Provisional Patent Application 60/461,232 to Gross et al., filed Apr. 8,2003.

The '508 application claims priority from (a) U.S. Provisional PatentApplication 60/388,931, filed Jun. 14, 2002, and (b) U.S. patentapplication Ser. No. 10/294,310 to Gross et al., filed Nov. 14, 2002,which claims priority from: (i) U.S. Provisional Patent Application60/400,167, filed Jul. 31, 2002, and (ii) U.S. Provisional PatentApplication 60/364,451, filed Mar. 15, 2002.

The '113 application (a) claims priority from U.S. Provisional PatentApplication 60/506,165, filed Sep. 26, 2003, and (b) is acontinuation-in-part of U.S. patent application Ser. No. 10/258,714,filed Jan. 22, 2003, which is a US national phase application ofInternational Patent Application PCT/IL01/00402, filed May 7, 2001,which claims priority from U.S. Provisional Patent Application60/203,172, filed May 8, 2000.

All of the above-mentioned applications are assigned to the assignee ofthe present application and are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to medical procedures andelectronic devices. More specifically, the invention relates to the useof electrical devices for implantation in the head, for example, in thenasal cavity. The invention also relates to methods for using odorantsto induce or to inhibit neural activity for the treatment and/ordiagnosis of a clinical condition. The invention also relates toapparatus and methods for administering drugs, for treating stroke andheadaches such as migraine and cluster headaches, and for improvingcerebral blood flow.

BACKGROUND OF THE INVENTION

The blood-brain barrier (BBB) is a unique feature of the central nervoussystem (CNS) which isolates the brain from the systemic bloodcirculation. To maintain the homeostasis of the CNS, the BBB preventsaccess to the brain of many substances circulating in the blood.

The BBB is formed by a complex cellular system of endothelial cells,astroglia, pericytes, perivascular macrophages, and a basal lamina.Compared to other tissues, brain endothelia have the most intimatecell-to-cell connections: endothelial cells adhere strongly to eachother, forming structures specific to the CNS called “tight junctions”or zonula occludens. They involve two opposing plasma membranes whichform a membrane fusion with cytoplasmic densities on either side. Thesetight junctions prevent cell migration or cell movement betweenendothelial cells. A continuous uniform basement membrane surrounds thebrain capillaries. This basal lamina encloses contractile cells calledpericytes, which form an intermittent layer and probably play some rolein phagocytosis activity and defense if the BBB is breached. Astrocyticend feet, which cover the brain capillaries, build a continuous sleeveand maintain the integrity of the BBB by the synthesis and secretion ofsoluble growth factors (e.g., gamma-glutamyl transpeptidase) essentialfor the endothelial cells to develop their BBB characteristics.

Because of the BBB, certain non-surgical treatments of the brain basedupon systemic introduction of compounds through the bloodstream havebeen ineffective or less effective. For example, chemotherapy has beenrelatively ineffective in the treatment of CNS metastases of systemiccancers (e.g., breast cancer, small cell lung cancer, lymphoma, and germcell tumors), despite clinical regression and even complete remission ofthese tumors in non-CNS systemic locations. The most important factorsdetermining drug delivery from blood into the CNS are lipid solubility,molecular mass, and electrical charge. A good correlation exists betweenthe lipid solubility of a drug, expressed as the octanol/water partitioncoefficient, and the drug's ability to penetrate or diffuse across theBBB. This is particularly relevant for drugs with molecular weightssmaller than 600 dalton (Da). The normal BBB prevents the passage ofionized water soluble drugs with a molecular weight greater than 180 Da.Most currently-available effective chemotherapeutic agents, however,have a molecular weight between 200 and 1200 Da. Therefore, based bothon their lipid solubilities and molecular masses, the passage of manyagents is impeded by the BBB.

In addition to transcellular diffusion of lipophilic agents, there areseveral specific transport mechanisms to carry certain molecules acrossthe brain's endothelial cells. Specific transport proteins exist forrequired molecules, such as glucose and amino acids. Additionally,absorptive endocytosis and transcytosis occur for cationized plasmaproteins. Specific receptors for certain proteins, such as transferrinand insulin, mediate endocytosis and transport across the cell.

Non-surgical treatment of neurological disorders is generally limited tosystemic introduction of compounds such as neuropharmaceuticals andother neurologically-active agents that might remedy or modifyneurologically-related activities and disorders. Such treatment islimited, however, by the relatively small number of known compounds thatpass through the BBB. Even those that do cross the BBB often produceadverse reactions in other parts of the body or in non-targeted regionsof the brain.

There have been a number of different studies regarding efforts to crossthe BBB—specifically, with regard to overcoming the limited access ofdrugs to the brain. Such efforts have included, for example, chemicalmodification, development of more hydrophobic analogs, or linking anactive compound to a specific carrier. Transient opening of the BBB inhumans has been achieved by intracarotid infusion of hypertonic mannitolsolutions or bradykinin analogs. Also, modulation of the P-glycoprotein,whose substrates are actively pumped out of brain cells into capillarylumens, has been found to facilitate the delivery of drugs to the brain.However, due to the inherent limitations of each of the aforementionedprocedures, there is still a need for more generic, effective, andpredictable ways to cross the BBB.

It would also be desirable to develop controllable means for modulatingcerebral blood flow. Many pathological conditions, such as stroke,migraine, and Alzheimer's disease, are significantly affected orexacerbated by abnormal cerebral blood flow.

Alzheimer's disease (AD) is the most common form of both senile andpresenile dementia in the world and is recognized clinically asrelentlessly progressive loss of memory and intellectual function anddisturbances in speech (Merritt, 1979, A Textbook of Neurology, 6thedition, pp. 484-489, Lea & Febiger, Philadelphia, which is incorporatedherein by reference). Alzheimer's disease begins with mildlyinappropriate behavior, uncritical statements, irritability, a tendencytowards grandiosity, euphoria, and deteriorating performance at work; itprogresses through deterioration in operational judgment, loss ofinsight, depression, and loss of recent memory; and it ends in severedisorientation and confusion, apraxia of gait, generalized rigidity, andincontinence (Gilroy & Meyer, 1979, Medical Neurology, pp. 175-179,MacMillan Publishing Co., which is incorporated herein by reference,).Alzheimer's disease is found in about 10% of the population over the ageof 65 and 47% of the population over the age of 85 (Evans et al., 1989,JAMA, 262: 2551-2556, which is incorporated herein by reference).

Alzheimer's Disease is characterized by the accumulation of insoluble,10 nm filaments containing β-amyloid (Aβ) peptides, localized in theextracellular space of the cerebral cortex and vascular walls. These 40or 42 amino acid long Aβ peptides are derived from the larger β-amyloidprecursor protein (βAPP) through the endopeptidase action of β and γsecretases. In addition, the post-translational action of putativeaminopeptidases results in a heterogeneous shortening of the 40 or 42amino acid long Aβ peptides that either terminate at residue 40 or 42and, therefore, are designated as ApN-40 and AβN-42. In familial formsof AD, the pathological appearance of the Aβ peptides in the brain isdriven by the presence of mutations in the βAPP gene or in the genescoding for the proteins presenilin 1 and 2.

Sporadic AD accounts for more than 95% of the known AD cases. Itsetiology, however, remains obscure. An accepted view is that sporadic ADresults from the interplay between an individual's genetic factors andthe environment, leading to the deposition of Aβ, neurodegeneration, anddementia. Despite this emerging perspective, insufficient effort hasbeen made in identifying factors responsible for Aβ accumulation in thebrain.

The etiology of Alzheimer's disease is unknown. Evidence for a geneticcontribution comes from several important observations such as thefamilial incidence, pedigree analysis, monozygotic and dizygotic twinstudies, and the association of the disease with Down's syndrome (forreview see Baraitser, 1990, The Genetics of Neurological Disorders, 2ndedition, pp. 85-88, which is incorporated herein by reference).Nevertheless, this evidence is far from definitive, and it is clear thatother factors are involved.

Alzheimer's Disease is a neurodegenerative disease characterized by aprogressive decline of cognitive functions, including loss ofdeclarative and procedural memory, decreased learning ability, reducedattention span, and severe impairment in thinking ability, judgment, anddecision making. Mood disorders and depression are also often observedin AD patients. It is estimated that AD affects about 4 million peoplein the USA and 20 million people worldwide. Because AD is an age-relateddisorder (with an average onset at 65 years), the incidence of thedisease in industrialized countries is expected to rise dramatically asthe population of these countries ages.

AD is characterized by the following neuropathological features:

-   -   massive loss of neurons and synapses in the brain regions        involved in higher cognitive functions (association cortex,        hippocampus, amygdala). Cholinergic neurons are particularly        affected.    -   neuritic (senile) plaques that are composed of a core of amyloid        material surrounded by a halo of dystrophic neurites, reactive        type I astrocytes, and numerous microglial cells (Selkoe, D. J.,        Annu Rev Neurosci 17: 489-517, 1994; Selkoe, D. J., J        Neuropathol Exp Neurol 53: 438-447, 1994; Dickson, D. W., J        Neuropathol Exp Neurol 56: 321-339, 1997; Hardy, J. et al.,        Science 282: 1075-1079, 1998; Selkoe, D. J., Cold Spring Harb        Symp Quant Biol 61: 587-596, 1996, all of which are incorporated        herein by reference. The major component of the core is a        peptide of 39 to 42 amino acids called the amyloid P protein, or        Aβ. Although the Aβ protein is produced by the intracellular        processing of its precursor, APP, the amyloid deposits forming        the core of the plaques are extracellular. Studies have shown        that the longer form of Aβ (Aβ42) is much more amyloidogenic        than the shorter forms (Aβ40 or Aβ39).    -   neurofibrillary tangles that are composed of paired-helical        filaments (PHF) (Ray et al., Mol Med Today 4: 151-157, 1998;        Brion, Acta Neurol Belg 98: 165-174, 1998, both of which are        incorporated herein by reference). Biochemical analyses revealed        that the main component of PHF is a hyper-phosphorylated form of        the microtubule-associated protein τ. These tangles are        intracellular structures, found in the cell body of dying        neurons, as well as some dystrophic neurites in the halo        surrounding neuritic plaques. Both plaques and tangles are found        in the same brain regions affected by neuronal and synaptic        loss.

Although the neuronal and synaptic loss is universally recognized as theprimary cause of the decline of cognitive functions, the cellular,biochemical, and molecular events responsible for this neuronal andsynaptic loss are subject to fierce controversy. The number of tanglesshows a better correlation than the amyloid load with the cognitivedecline (Albert, Proc Natl Acad Sci USA 93: 13547-13551, 1996, which isincorporated herein by reference). On the other hand, a number ofstudies showed that amyloid can be directly toxic to neurons, resultingin behavioral impairment (Ma et al., Neurobiol Aging 17: 773-780, 1996,which is incorporated herein by reference). It has also been shown thatthe toxicity of some compounds (amyloid or tangles) could be aggravatedby activation of the complement cascade, suggesting the possibleinvolvement of inflammatory process in the neuronal death.

Genetic and molecular studies of some familial forms of AD (FAD) haverecently provided evidence that boosted the amyloid hypothesis (Ii,Drugs Aging 7: 97-109, 1995; Price et al., Curr Opin Neurol 8: 268-274,1995; Hardy, Trends Neurosci 20: 154-159, 1997; Selkoe, J Biol Chem 271:18295-18298, 1996, all of which are incorporated herein by reference).The assumption is that since the deposition of Aβ in the core of senileplaques is observed in all Alzheimer cases, if Aβ is the primary causeof AD, then mutations that are linked to FAD should induce changes that,in one way or another, foster Aβ deposition. There are 3 FAD genes knownso far (Hardy et al., Science 282: 1075-1079, 1998; Ray et al., Mol MedToday 4: 151-157, 1998, both of which are incorporated herein byreference), and the activity of all of them results in increased Aβdeposition, a very compelling argument in favor of the amyloidhypothesis.

The first of the 3 FAD genes codes for the Aβ precursor, APP (Selkoe, JBiol Chem 271: 18295-18298, 1996, which is incorporated herein byreference). Mutations in the APP gene are very rare, but all of themcause AD with 100% penetrance and result in elevated production ofeither total Aβ or Aβ42, both in vitro (transfected cells) and in vivo(transgenic animals). The other two FAD genes code for presenilin 1 and2 (PS1, PS2) (Hardy, Trends Neurosci 20: 154-159, 1997, which isincorporated herein by reference). The presenilins contain 8transmembrane domains and several lines of evidence suggest that theyare involved in intracellular protein trafficking, although their exactfunction is still unknown. Mutations in the presenilin genes are morecommon than in the APP genes, and all of them also cause FAD with 100%penetrance. In addition, in vitro and in vivo studies have demonstratedthat PS1 and PS2 mutations shift APP metabolism, resulting in elevatedAβ42 production. For a recent review on the genetics of AD, see Lippa, JMol Med 4: 529-536, 1999, which is incorporated herein by reference.

In spite of these compelling genetic data, it is still unclear whetherAβ generation and amyloid deposition are the primary cause of neuronaldeath and synaptic loss observed in AD. Moreover, the biochemical eventsleading to Aβ production, the relationship between APP and thepresenilins, and between amyloid and neurofibrillary tangles are poorlyunderstood. Thus, the picture of interactions between the majorAlzheimer proteins is very incomplete, and it is clear that a largenumber of novel proteins are yet to be discovered.

The diagnosis of Alzheimer's disease at autopsy is definitive. Grosspathological changes are found in the brain, including low weight andgeneralized atrophy of both the gray and white matter of the cerebralcortex, particularly in the temporal and frontal lobes (Adams & Victor,1977, Principles of Neurology, pp. 401-407 and Merritt, 1979, A Textbookof Neurology, 6th edition, Lea & Febiger, Philadelphia, pp. 484-489,both of which are incorporated herein by reference). The histologicalchanges include neurofibrillary tangle (Kidd, Nature 197: 192-193, 1963;Kidd, Brain 87: 307-320, 1964, both of which are incorporated herein byreference), which consists of a tangled mass of paired helical andstraight filaments in the cytoplasm of affected neurons (Oyanagei, Adv.Neurol. Sci. 18: 77-88, 1979 and Grundke-Iqbal et al., Acta Neuropathol.66: 52-61, 1985, both of which are incorporated herein by reference).

The diagnosis of Alzheimer's disease during life is more difficult thanat autopsy since the diagnosis depends upon inexact clinicalobservations. In the early and middle stages of the disease, thediagnosis is based on clinical judgment of the attending physician. Inthe late stages, where the symptoms are more recognizable, clinicaldiagnosis is more straightforward. But, in any case, before anunequivocal diagnosis can be made, other diseases, with partiallyoverlapping symptoms, must be ruled out. Usually a patient must beevaluated on a number of occasions to document the deterioration inintellectual ability and other signs and symptoms. The necessity forrepeated evaluation is costly, generates anxiety, and can be frustratingto patients and their families. Furthermore, the development of anappropriate therapeutic strategy is hampered by the difficulties ofrapid diagnosis, particularly in the early stages where earlyintervention could leave the patient with significant intellectualcapacity and a reasonable quality of life. In brief, no unequivocallaboratory test specific for Alzheimer's disease has been reported.

Alzheimer's disease is associated with degeneration of cholinergicneurons, in the basal forebrain, which play a fundamental role incognitive functions, including memory (Becker et al., Drug DevelopmentResearch 12: 163-195, 1988, which is incorporated herein by reference).Progressive, inexorable decline in cholinergic function and cholinergicmarkers in the brain of Alzheimer's disease patients has been observedin numerous studies, and includes, for example, a marked reduction inacetylcholine synthesis, choline acetyltransferase activity,acetylcholinesterase activity, and choline uptake (Davis, Brain Res.171: 319-327, 1979 and Hardy et al., Neurochem. Int. 7: 545-563, 1985,which are incorporated herein by reference). Even more, decreasedcholinergic function may be an underlying cause of cognitive declineseen in Alzheimer's-disease patients (Kish et al., J. Neurol.,Neurosurg., and Psych. 51: 544-548, 1988, which is incorporated hereinby reference). Choline acetyltransferase and acetylcholinesteraseactivities decrease significantly as plaque count rises, and, indemented subjects, the reduction in choline acetyl transferase activitywas found to correlate with intellectual impairment (Perry, et al.,Brit. Med. J. 25, November 1978, p. 1457, which is incorporated hereinby reference).

Nerve cells produce nerve growth factors, proteins that regulate cellmaturation during prenatal development and also play an important rolein cell survival, repair, and regeneration during adult life. Because oftheir significance in cell maintenance and repair, these factors haveattracted attention as potential treatments in Alzheimer's disease,stroke, spinal cord injury, and other neurodegenerative conditions.However, nerve growth factors are usually too large to cross theblood-brain barrier (BBB), a protective shield that restricts passage ofmolecules to the brain.

The BBB is functionally situated at the brain capillaries endotheliumlayer and covers a surface area of 12 m2/g of brain parenchyma. Thetotal length of this capillary network is 650 km. The cerebral capillaryendothelial cell displays some peculiar morphologic characteristics thatform the anatomic basis of the blood-brain barrier. It differs from theperipheral capillary endothelial cell (referring to all non-CNS sites)in a number of ways:

First, the CNS endothelial cell layer is not fenestrated. Cells arejoined by tight junctions composed of 6 to 8 pentalaminar structures.They actively block protein movements, hydrophilic transfer and evenionic diffusion. Thus, there is very little movement of compoundsbetween endothelial cells from the blood to the CNS.

Second, and in contrast to the peripheral capillary endothelial cell,transcellular movement of molecules through the non-specific mechanismof fluid-phase endocytosis is generally absent. The cerebral vascularendothelial cell possesses a transcellular lipophilic pathway, allowingdiffusion of small lipophilic compounds. In addition to this route,specific receptor-mediated transport systems are present for givenmolecules, like insulin, transferrin, glucose, purines and amino acids.These transport systems are highly selective and asymmetric.

Third, the CNS endothelial cell displays a net negative charge at itsendoluminal side and at the basement membrane. This provides anadditional selective mechanism by impeding anionic molecules to crossthe membrane.

Fourth, the cerebral endothelial cell has very few pinocytic vesicles,and these vesicles are not involved in any transport function.

Fifth, astrocyte foot processes surround the microvascular endotheliumand cover more than 95 percent of its surface, therefore interposingbetween capillaries and cerebral neuropil.

By virtue of this selective barrier, the CNS can preferentially regulatethe extracellular concentration of certain solutes, growth factors andneurotransmitters, keep certain molecules in the CNS and isolate itselffrom some others, and further isolate itself from sudden systemichomeostatic changes. It is therefore an integral component of themechanisms involved in the tight regulation of the extra-cellularhomeostasis necessary to the normal CNS function. This relativelyimpermeable barrier has some drawbacks, however, when considering thetherapeutic delivery of a molecule to the CNS.

The delivery of therapeutic molecules across the BBB has proven to be amajor obstacle in treating various brain disorders. The normalblood-brain barrier prevents passage of ionized water-soluble compoundswith a molecular weight greater than 180 Daltons. Therefore, the BBB isa major impediment to the treatment of CNS diseases as many drugs areunable to reach this organ at therapeutic concentrations. More than 98%of the CNS-targeted drugs do not cross the BBB. Example of suchdisorders are: primary brain tumors, metastatic brain tumors, AD,addiction, ALS, head injury, Huntington's disease, multiple sclerosis(MS), depression, Cerebral Palsy, schizophrenia, epilepsy, stress andanxiety. Many new neurotherapeutic agents are being discovered, butbecause of a lack of suitable strategies for drug delivery across theBBB, these agents are ineffective. Such drugs will only become effectiveif strategies for brain delivery are developed in parallel.

Apart from molecular parameters, the permeability of the BBB and activetransport mechanisms, a major determinant of molecular transport acrossthe BBB is their concentration gradient—between the CNS and the cerebralcirculation.

Additionally, the functioning BBB inhibits clearance of neurotoxiccompounds, such as β-Amyloid, tau, PS1, and PS2, from the CNS into thesystemic circulation. These neurotoxic compounds are therefore notmetabolized and removed from the body to the extent desired, andtherefore continue to have undesired effects in the CNS.

PCT Publication WO 01/85094 and U.S. Patent Application Publication2004/0015068 to Shalev and Gross, which are assigned to the assignee ofthe present patent application and are incorporated herein by reference,describe apparatus for modifying a property of a brain of a patient,including electrodes applied to a sphenopalatine ganglion (SPG) or aneural tract originating in or leading to the SPG. A control unit drivesthe electrodes to apply a current capable of inducing (a) an increase inpermeability of a blood-brain barrier (BBB) of the patient, (b) a changein cerebral blood flow of the patient, and/or (c) an inhibition ofparasympathetic activity of the SPG.

PCT Publication WO 04/010923 to Gross et al., which is assigned to theassignee of the present application and is incorporated herein byreference, describes a chemical agent delivery system including achemical agent supplied to a body of a subject for delivery to a site ina central nervous system of said subject via blood of said subject; anda stimulator for stimulating parasympathetic fibers associated with thesphenopalatine ganglion, thereby to render a blood brain barrier (BBB)of said subject permeable to said chemical agent during at least aportion of the time that said chemical agent is present in said blood.

PCT Publication WO 04/043218 to Gross et al., which is assigned to theassignee of the present application and is incorporated herein byreference, describes treatment apparatus comprising (a) a stimulationdevice, adapted to be implanted in a vicinity of a site selected fromthe list consisting of: a sphenopalatine ganglion (SPG) of the subjectand a neural tract originating in or leading to the SPG; and (b) aconnecting element, coupled to the stimulation device, and adapted to bepassed through at least a portion of a greater palatine canal of thesubject. Also described is a method for implanting a treatmentstimulation device in a vicinity of a site of a subject, the methodcomprising passing the device through a greater palatine foramen of thesubject, and bringing the device into contact with the vicinity of thesite, the site selected from the list consisting of: a sphenopalatineganglion (SPG) of the subject and a neural tract originating in orleading to the SPG.

PCT Publication WO 04/044947 to Gross et al., which is assigned to theassignee of the present application and is incorporated herein byreference, describes apparatus for use with an implanted medical devicehaving two conductive elements in contact with tissue of a subject. Theapparatus comprises a shunt, electrically coupled between the conductiveelements, the shunt adapted to be in a first state when the subject isexposed to a source of radiofrequency (RF) energy, and adapted to be ina second state when the subject is not exposed to the RF energy, theshunt being characterized such that in the first state the shunt has afirst impedance, and in the second state the shunt has a secondimpedance at least two times greater than the first impedance.

U.S. Patent Application Publication 2003/0176898 and PCT Publication WO04/043217 to Gross et al., which are assigned to the assignee of thepresent application and are incorporated herein by reference, describeapparatus for treating a condition of an eye of a subject, comprising astimulator adapted to stimulate at least one site of the subject, so asto treat the eye condition, the site selected from the list consistingof: a sphenopalatine ganglion (SPG) of the subject, an anteriorethmoidal nerve of the subject, a posterior ethmoidal nerve of thesubject, a communicating branch between an anterior ethmoidal nerve anda retro-orbital branch of an SPG of the subject, a communicating branchbetween a posterior ethmoidal nerve and a retro-orbital branch of an SPGof the subject, a greater palatine nerve of the subject, a lesserpalatine nerve of the subject, a sphenopalatine nerve of the subject, acommunicating branch between a maxillary nerve and an SPG of thesubject, a nasopalatine nerve of the subject, a posterior nasal nerve ofthe subject, an infraorbital nerve of the subject, an otic ganglion ofthe subject, an afferent fiber going into the otic ganglion of thesubject, an efferent fiber going out of the otic ganglion of thesubject, a vidian nerve of the subject, a greater superficial petrosalnerve of the subject, and a lesser deep petrosal nerve of the subject.

U.S. Patent Application Publication 2003/0176892 and PCT Publication WO04/043334 to Shalev, which are assigned to the assignee of the presentapplication and are incorporated herein by reference, describe apparatusfor delivering a Non Steroidal Anti-Inflammatory Drug (NSAID) suppliedto a body of a subject for delivery to at least a portion of a centralnervous system (CNS) of the subject via a systemic blood circulation ofthe subject, including a stimulator adapted to stimulate at least onesite of the subject, so as to cause an increase in passage of the NSAIDfrom the systemic blood circulation across a blood brain barrier (BBB)of the subject to the portion of the CNS, during at least a portion ofthe time that the NSAID is present in the blood, the site selected fromthe list consisting of: a sphenopalatine ganglion (SPG) of the subject,an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerveof the subject, a communicating branch between an anterior ethmoidalnerve and a retro-orbital branch of an SPG of the subject, acommunicating branch between a posterior ethmoidal nerve and aretro-orbital branch of an SPG of the subject, a greater palatine nerveof the subject, a lesser palatine nerve of the subject, a sphenopalatinenerve of the subject, a communicating branch between a maxillary nerveand an SPG of the subject, a nasopalatine nerve of the subject, aposterior nasal nerve of the subject, an infraorbital nerve of thesubject, an otic ganglion of the subject, an afferent fiber going intothe otic ganglion of the subject, an efferent fiber going out of theotic ganglion of the subject, a vidian nerve of the subject, a greatersuperficial petrosal nerve of the subject, and a lesser deep petrosalnerve of the subject.

PCT Publication WO 04/045242 to Shalev et al., which is assigned to theassignee of the present application and is incorporated herein byreference, describes apparatus for treating a condition of an ear of asubject, comprising a stimulator adapted to stimulate at least one siteof the subject at a level sufficient to treat the ear condition, thesite selected from the list consisting of: an otic ganglion of thesubject, an afferent fiber going into the otic ganglion of the subject,an efferent fiber going out of the otic ganglion of the subject, asphenopalatine ganglion (SPG) of the subject, an anterior ethmoidalnerve of the subject, a posterior ethmoidal nerve of the subject, acommunicating branch between an anterior ethmoidal nerve and aretro-orbital branch of an SPG of the subject, a communicating branchbetween a posterior ethmoidal nerve and a retro-orbital branch of an SPGof the subject, a greater palatine nerve of the subject, a lesserpalatine nerve of the subject, a sphenopalatine nerve of the subject, acommunicating branch between a maxillary nerve and an SPG of thesubject, a nasopalatine nerve of the subject, a posterior nasal nerve ofthe subject, an infraorbital nerve of the subject, a vidian nerve of thesubject, a greater superficial petrosal nerve of the subject, and alesser deep petrosal nerve of the subject.

U.S. Pat. No. 5,756,071 to Mattem et al., which is incorporated hereinby reference, describes a method for nasally administering aerosols oftherapeutic agents to enhance penetration of the blood brain barrier.The patent describes a metering spray designed for pemasal application,the spray containing at least one sex hormone or at least one metabolicprecursor of a sex hormone or at least one derivative of a sex hormoneor combinations of these, excepting the precursors of testosterone, orat least one biogenic amine, with the exception of catecholamines.

U.S. Pat. No. 5,752,515 to Jolesz et al., which is incorporated hereinby reference, describes apparatus for image-guided ultrasound deliveryof compounds through the blood-brain barrier. Ultrasound is applied to asite in the brain to effect in the tissues and/or fluids at thatlocation a change detectable by imaging. At least a portion of the brainin the vicinity of the selected location is imaged, e.g., via magneticresonance imaging, to confirm the location of that change. A compound,e.g., a neuropharmaceutical, in the patients bloodstream is delivered tothe confirmed location by applying ultrasound to effect opening of theblood-brain barrier at that location and, thereby, to induce uptake ofthe compound there.

PCT Publication WO 01/97905 to Ansarinia, which is incorporated hereinby reference, describes a method for the suppression or prevention ofvarious medical conditions, including pain, movement disorders,autonomic disorders, and neuropsychiatric disorders. The method includespositioning an electrode on or proximate to at least one of thepatient's SPG, sphenopalatine nerves, or vidian nerves, and activatingthe electrode to apply an electrical signal to such nerve. In a furtherembodiment for treating the same conditions, the electrode used isactivated to dispense a medication solution or analgesic to such nerve.The '905 publication also describes surgical techniques for implantingthe electrode.

U.S. Pat. No. 6,405,079 to Ansarinia, which is incorporated herein byreference, describes a method for the suppression or prevention ofvarious medical conditions, including pain, movement disorders,autonomic disorders, and neuropsychiatric disorders. The method includespositioning an electrode adjacent to or around a sinus, the duraadjacent a sinus, or falx cerebri, and activating the electrode to applyan electrical signal to the site. In a further embodiment for treatingthe same conditions, the electrode dispenses a medication solution oranalgesic to the site. The '079 patent also describes surgicaltechniques for implanting the electrode.

U.S. Patent Application Publication 2002/0052311 to Solomon et al.,which is incorporated herein by reference, describes methods fortreating and/or diagnosing neurological conditions of the CNS. Someembodiments include displaying a therapeutic molecule capable oftreating the condition on a viral display vehicle and introducing thevehicle into a subject in need thereof by applying the viral displayvehicle to an olfactory system of the subject.

PCT Publication WO 02/094191 to Wisniewski et al., which is incorporatedherein by reference, describes techniques for diagnosing Alzheimer'sdisease in vivo using magnetic resonance imaging. A labeled A-betapeptide or its derivative is injected into the patient to be diagnosed,after which the patient is subjected to magnetic resonance imaging.

U.S. Pat. No. 5,059,415 to Neuwelt, which is incorporated herein byreference, describes a method for diagnosing and characterizing brainlesions by first chemically modifying the blood-brain barrier (BBB) inorder to increase BBB permeability. Thereafter, a chemical agent (e.g.,mAb or pAb) is introduced which binds to brain lesions.

U.S. Pat. No. 4,866,042 to Neuwelt, which is incorporated herein byreference, describes a method for treating genetic and acquired braindisorders by introducing genetic material into the blood stream fordelivery to the brain. Prior to delivery, the interendothelial structureof the BBB is chemically altered to permit passage of the geneticmaterial therethrough.

U.S. Pat. No. 6,117,454 to Kreuter et al., which is incorporated hereinby reference, describes a method for delivering drugs and diagnosticsacross the BBB or blood-nerve barrier by incorporating these agents intonanoparticles which have been fabricated in conventional ways and thencoated with an additional surfactant.

PCT Publication WO 00/73343 to Soreq et al., which is incorporatedherein by reference, describes techniques for diagnosing CNS stress,elevated glucocorticoid level, disruption of the blood-brain barrier orAlzheimer's disease, by testing a blood sample using antibodiesrecognizing acetylcholinesterase or a C-terminal peptide derived fromacetylcholinesterase.

U.S. Pat. No. 5,268,164 to Kozarich et al., which is incorporated hereinby reference, describes techniques for using polypeptides calledreceptor mediated permeabilizers to increase the permeability of theblood-brain barrier to molecules such as therapeutic agents ordiagnostic agents.

U.S. Pat. No. 6,005,004 to Katz et al., which is incorporated herein byreference, describes site-specific biomolecular complexes comprising atherapeutic, prophylactic and diagnostic agent, and an omega-3 fattyacid and derivatives thereof, which complexes are covalently bonded withcationic carriers and permeabilizer peptides for delivery across the BBBand with targeting moieties for uptake by target brain cells.

U.S. Pat. No. 5,833,988 to Friden, which is incorporated herein byreference, describes a method for delivering a neuropharmaceutical ordiagnostic agent across the BBB to the brain. The method comprisesadministering to the host a therapeutically effective amount of anantibody-neuropharmaceutical or diagnostic agent conjugate wherein theantibody is reactive with a transferrin receptor.

The following references, which are incorporated herein by reference,may be useful:

-   Delepine L, Aubineau P, “Plasma protein extravasation induced in the    rat dura mater by stimulation of the parasympathetic sphenopalatine    ganglion,” Experimental Neurology, 147, 389-400 (1997)-   Hara H, Zhang Q J, Kuroyanagi T, Kobayashi S, “Parasympathetic    cerebrovascular innervation: An anterograde tracing from the    sphenopalatine ganglion in the rat,” Neurosurgery, 32, 822-827    (1993)-   Jolliet-Riant P, Tillement JP, “Drug transfer across the blood-brain    barrier and improvement of brain delivery,” Fundam. Clin.    Pharmacol., 13, 16-25 (1999)-   Kroll RA, Neuwelt EA, “Outwitting the blood brain barrier for    therapeutic purposes: Osmotic opening and other means,”    Neurosurgery, 42, 1083-1100 (1998)-   Sanders M, Zuurmond WW, “Efficacy of sphenopalatine ganglion    blockade in 66 patients suffering from cluster headache: A 12-70    month follow-up evaluation,” Journal of Neurosurgery, 87, 876-880    (1997)-   Syelaz J, Hara H, Pinard E, Mraovitch S, MacKenzie ET, Edvinsson L,    “Effects of stimulation of the sphenopalatine ganglion on cortical    blood flow in the rat,” Journal of Cerebral Blood Flow and    Metabolism,” 8, 875-878 (1988)-   Van de Waterbeemd H, Camenisch G, Folkers G, Chretien JR, Raevsky    OA, “Estimation of blood brain barrier crossing of drugs using    molecular size and shape and h bonding descriptors,” Journal of Drug    Targeting,” 6, 151-165, (1998)-   Suzuki N, Hardebo JE, Kahrstrom J, Owman C, “Selective electrical    stimulation of postganglionic cerebrovascular parasympathetic nerve    fibers originating from the sphenopalatine ganglion enhances    cortical blood flow in the rat,” Journal of Cerebral Blood Flow and    Metabolism, 10, 383-391 (1990)-   Suzuki N, Hardebo JE, Kahrstrom J, Owman CH, “Effect on cortical    blood flow of electrical stimulation of trigeminal cerebrovascular    nerve fibres in the rat,” Acta Physiol. Scand., 138, 307-315 (1990)-   Major A, Silver W, “Odorants presented to the rat nasal cavity    increase cortical blood flow,” Chem. Senses, 24, 665-669 (1999)-   Fusco B M, Fiore G, Gallo F, Martelletti P, Giacovazzo M,    “‘Capsaicin-sensitive’ sensory neurons in cluster headache:    pathophysiological aspects and therapeutic indications,” Headache,    34, 132-137 (1994)-   Lambert G A, Bogduk N, Goadsby PJ, Duckworth JW, Lance JW,    “Decreased carotid arterial resistance in cats in response to    trigeminal stimulation,” Journal of Neurosurgery, 61, 307-315 (1984)-   Silver W L, “Neural and pharmacological basis for nasal irritation,”    in Tucker WG, Leaderer BP, Mølhave L, Cain WS (eds), Sources of    Indoor Air Contaminants, Ann. NY Acad. Sci., 641, 152-163 (1992)-   Silver W, “Chemesthesis: the burning questions,” ChemoSense, Vol. 2    No. 1, 1-2 (1999)-   Asaba H, Hosoya K, Takanaga H, Ohtsuki S, Tamura E, Takizawa T,    Terasaki T, “Blood-Brain barrier is involved in the efflux transport    of a neuroactive steroid, dehydroepiandrosterone sulfate, via    organic anion transporting polypeptide 2,” J. Neurochem. 75(5):    1907-1916 (2000)-   Isakovica AJ, Segalb MB, Milojkovica BA, Dacevica MP, Misirlica ST,    Rakicc ML, Redzicb ZB, “The efflux of purine nucleobases and    nucleosides from the rat brain,” Neuroscience Letters 318: 65-68    (2002)-   Kakee A, Terasaki T, Sugiyama Y, “Brain efflux index as a novel    method of analyzing efflux transport at the blood-brain barrier,” J.    Pharmacol. Exp. Ther. 277: 1550-1559(1996)-   Kakee A, Terasaki T, Sugiyama Y, “Selective brain to blood efflux    transport of para-aminohippuric acid across the blood-brain barrier:    in vivo evidence by use of the brain efflux index method,” J.    Pharmacol. Exp. Ther. 283: 1018-1025 (1997)-   Takasawa K, Terasaki T, Suzuki H, Sugiyama Y, “In vivo evidence for    carrier-mediated efflux transport of 39-azido-39-deoxythymidine and    29,39-dideoxyinosine across the blood-brain barrier via a    probenecid-sensitive transport system,” J. Pharmacol. Exp. Ther.    281: 369-375 (1997)-   Hosoya K, Sugawara M, Asaba H, Terasaki T, “Blood-brain barrier    produces significant efflux of L-aspartic acid, but not D-aspartic    acid: in vivo evidence using the brain efflux index method,” J.    Neurochem. 73: 1206-1211 (1999)-   Boado R J, “Antisense delivery through the blood brain barrier,”    Adv. Drug. Del. Rev. 15: 73-107 (1995)-   Devoghel J C, “Cluster headache and sphenopalatine block,” Acta    Anaesthesiol Belg., 32(1): 101-7 (1981)-   Tamano H et al., “Uptake of radioactive elements in rat brain    tumor,” RIKEN Review, No. 35 (May 2001)

OBJECTS OF THE INVENTION

It is an object of some aspects of the present invention to provideimproved methods and apparatus for delivery of compounds to the brain,particularly through the BBB.

It is also an object of some aspects of the present invention to providesuch methods and apparatus as can be employed to deliver such compoundsthrough the BBB with a minimally invasive approach.

It is a further object of some aspects of the present invention toprovide such methods and apparatus as can facilitate delivery of largemolecular weight compounds through the BBB.

It is yet a further object of some aspects of the present invention toprovide cost-effective methods and apparatus for delivery of compoundsthrough the blood-brain-barrier.

It is still a further object of some aspects of the present invention toprovide improved methods and apparatus for remedying or modifyingneurological activities and disorders via delivery of compounds throughthe blood-brain-barrier.

It is also a further object of some aspects of the present invention tomodulate cerebral blood flow.

It is an additional object of some aspects of the present invention toprovide improved methods and apparatus for treating stroke.

It is yet an additional object of some aspects of the present inventionto provide improved methods and apparatus for treating migraine, clusterand other types of headaches.

It is still an additional object of some aspects of the presentinvention to provide improved methods and apparatus for treating and/orpreventing neurological diseases (for example, Alzheimer's disease),whose prognosis and evolution of pathological symptoms are influenced bycerebral blood flow.

It is also an object of some aspects of the present invention to provideimplantable apparatus which affects a property of the brain, withoutactually being implanted in the brain.

It is a further object of some aspects of the present invention toprovide methods which affect a property of the brain without the use ofimplantable apparatus.

It is still an additional object of some aspects of the presentinvention to provide improved methods and apparatus for treating and/orpreventing Alzheimer's disease.

It is also an object of some aspects of the present invention to provideimproved methods and apparatus for diagnosing neurological diseases.

It is a further object of some aspects of the present invention toprovide improved methods and apparatus for diagnosing Alzheimer'sdisease.

It is yet a further object of some aspects of the present invention toaffect a property of the brain by using the neuroexcitatory and/orneuroinhibitory effects of odorants on nerves in the head.

These and other objects of the invention will become more apparent fromthe description of preferred embodiments thereof provided hereinbelow.

SUMMARY OF THE INVENTION

In preferred embodiments of the present invention, an electricalstimulator drives current into the sphenopalatine ganglion (SPG) or intorelated neuroanatomical structures, including neural tracts originatingor reaching the SPG, including outgoing and incoming parasympathetic andsympathetic tracts and other parasympathetic centers. Typically, thestimulator drives the current in order to control and/or modifySPG-related behavior, e.g., in order to induce changes in cerebral bloodflow and/or to modulate permeability of the blood-brain barrier (BBB).These embodiments may be used in many medical applications, such as, byway of illustration and not limitation, (a) the treatment ofcerebrovascular disorders such as stroke, (b) the treatment of migraine,cluster and other types of headaches, or (c) the facilitation of drugtransport across the BBB.

In the specification of the present patent application, unlessindication to the contrary is stated, stimulation of the SPG is to beunderstood to alternatively or additionally include stimulation of oneor more of the following nerves or ganglions:

-   -   an anterior ethmoidal nerve;    -   a posterior ethmoidal nerve;    -   a communicating branch between the anterior ethmoidal nerve and        the SPG (retro orbital branch);    -   a communicating branch between the posterior ethmoidal nerve and        the SPG (retro orbital branch)    -   a nerve of the pterygoid canal (also called a vidian nerve),        such as a greater superficial    -   a petrosal nerve (a preganglionic parasympathetic nerve) or a        lesser deep petrosal nerve (a postganglionic sympathetic nerve);    -   a greater palatine nerve;    -   a lesser palatine nerve;    -   a sphenopalatine nerve;    -   a communicating branch between the maxillary nerve and the        sphenopalatine ganglion;    -   a nasopalatine nerve;    -   a posterior nasal nerve;    -   an infraorbital nerve;    -   an otic ganglion;    -   an afferent fiber going into the otic ganglion; and/or    -   an efferent fiber going out of the otic ganglion.

The SPG is a neuronal center located in the brain behind the nose. Itconsists of parasympathetic neurons innervating the middle cerebral andanterior cerebral lumens, the facial skin blood vessels, and thelacrimal glands. Activation of this ganglion is believed to causevasodilation of these vessels. A second effect of such stimulation isthe opening of pores in the vessel walls, causing plasma proteinextravasation (PPE). This effect allows better transport of moleculesfrom within these blood vessels to surrounding tissue.

The middle and anterior cerebral arteries provide the majority of theblood supply to the cerebral hemispheres, including the frontal andparietal lobes in their entirety, the insula and the limbic system, andsignificant portions of the following structures: the temporal lobes,internal capsule, basal ganglia and thalamus. These structures areinvolved in many of the neurological and psychiatric diseases of thebrain, and preferred embodiments of the present invention are directedtowards providing improved blood supply and drug delivery to thesestructures.

There is also some animal evidence for the presence of SPG-originatedparasympathetic innervation in the posterior cerebral and basilararteries. Consistent with the assumption that this is also the case inhumans, many regions of the human brain are within the reach oftreatments provided by preferred embodiments of the present invention,as described hereinbelow.

Currently the SPG is a target of manipulation in clinical medicine,mostly in attempted treatments of severe headaches such as clusterheadaches. The ganglion is blocked either on a short-term basis, byapplying lidocaine, or permanently, by ablation with a radio frequencyprobe. In both cases the approach is through the nostrils. In somepreferred embodiments of the present invention, similar methods forapproaching the SPG are utilized, to enable the electrical stimulationor electrical blocking thereof.

According to a preferred embodiment of the instant invention, a methodand apparatus are provided to enhance delivery of therapeutic moleculesacross the BBB by stimulation of the SPG and/or its outgoingparasympathetic tracts and/or another parasympathetic center. Theapparatus typically stimulates the parasympathetic nerve fibers of theSPG, thereby inducing the middle and anterior cerebral arteries todilate, and also causing the walls of these cerebral arteries to becomemore permeable to large molecules. In this manner, the movement of largepharmaceutical molecules from within blood vessels to the cerebraltissue is substantially increased. Preferably, therefore, this methodcan serve as a neurological drug delivery facilitator, without thesacrifices in molecular weight required by techniques of the prior art.In general, it is believed that substantially all pharmacologicaltreatments aimed at cerebral cells for neurological and psychiatricdisorders are amenable for use with these embodiments of the presentinvention. In particular, these embodiments may be adapted for use inthe treatment of disorders such as brain tumors, epilepsy, Parkinson'sdisease, Alzheimer's disease, multiple sclerosis, schizophrenia,depression, stress, obesity, pain, anxiety, and any other CNS disordersthat are directly or indirectly affected by changes in cerebral bloodflow or by BBB permeability changes.

Advantageously (and even in the absence of BBB permeability changes),patients with these and other disorders are generally helped by thevasodilation secondary to stimulation of the SPG, and the resultantimprovement in oxygen supply to neurons and other tissue. For someapplications, this treatment is given on a long-term basis, e.g., in thechronic treatment of Alzheimer's patients. For other applications, thetreatment is performed on a short-term basis, e.g., to minimize thedamage following an acute stroke event and initiate neuronal andtherefore functional rehabilitation.

Blocking of nerve transmission in the SPG or in related neural tracts isused in accordance with some preferred embodiments of the presentinvention to treat or prevent migraine headaches.

Alternatively or additionally, the changes induced by electricalstimulation as described hereinabove are achieved by presenting odorantsto an air passage of a patient, such as a nasal cavity or the throat.There is animal evidence that some odorants, such as propionic acid,cyclohexanone, and amyl acetate, significantly increase cortical bloodflow when presented to the nasal cavity. This has been interpreted bysome researchers as evidence that these odorants (e.g., environmentalpollutants) may be involved in the formation of various headaches byincreasing cerebral blood flow. The temporal profile and otherquantitative characteristics of such odorant stimulation are believed bythe present inventors to have a mechanism of action that has aneuroanatomical basis overlapping with that of the electricalstimulation of the SPG. Furthermore, experimental animal evidencecollected by the inventors and described in U.S. Provisional PatentApplication 60/368,657 to Shalev and Gross entitled, “SPG stimulation,”filed Mar. 28, 2002, which is assigned to the assignee of the presentinvention and is incorporated herein by reference, suggest a correlationbetween the mechanisms of increasing cerebral blood flow and increasedcerebrovascular permeability. It is hypothesized that such increasedcerebral blood flow caused by odorants is a result of stimulation ofparasympathetic and/or trigeminal fibers. These fibers may mediatecerebral blood flow changes directly, by communicating with the SPG, orby some other mechanism. It is also hypothesized that these odorantsstimulate via reflex arcs the SPG or other autonomic neural structuresthat innervate the cerebrovascular system. Therefore, the inventorshypothesize, odorant “stimulation” may increase cerebral blood flow ingeneral, and cortical blood flow in particular, by some or all of thesame mechanisms as electrical stimulation, as described hereinabove.Alternatively, odorants may cause increased cortical blood flow by othermechanisms, such as by entering the blood stream and reaching theaffected blood vessels in the brain or by parasympathetic stimulationvia the olfactory nerve. In addition to the effect on cerebral bloodflow, the introduction of odorants into an air passage is also expectedto induce an increase in the permeability of the anterior two thirds ofthe cerebrovascular system to circulating agents of various sizes, i.e.,to increase the permeability of the BBB. Similarly, presenting certainother odorants to an air passage decreases cerebral blood flow anddecreases the permeability of the BBB.

Odorants that may increase or decrease cerebral blood flow and/or thepermeability of the BBB include, but are not limited to, propionic acid,cyclohexanone, amyl acetate, acetic acid, citric acid, carbon dioxide,sodium chloride, ammonia, menthol, alcohol, nicotine, piperine,gingerol, zingerone, allyl isothiocyanate, cinnamaldehyde,cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate, thymol, andeucalyptol.

For some applications, delivery across the BBB of a pharmacologicalagent is enhanced by presenting an odorant to an air passage of apatient, such as a nasal cavity or the throat. Ln the context of thepresent patent application and in the claims, a pharmacological agent isan agent, for administration to a patient, that is made usingpharmacological procedures. Pharmacological agents may thus include, byway of illustration and not limitation, therapeutic agents and agentsfor facilitating diagnostic procedures.

According to a preferred embodiment of the instant invention, a methodis provided to enhance delivery of therapeutic molecules across the BBBby presenting an odorant to an air passage of a patient, such as a nasalcavity or the throat. In a preferred application, this method serves asa neurological drug delivery facilitator. The odorant is preferablypresented using apparatus known in the art, such as aqueous spray nasalinhalers; metered dose nasal inhalers; or air-dilution olfactometers.Alternatively or additionally, the odorant is presented by means of anorally-dissolvable capsule that releases the active odorants uponcontact with salivary liquids. The odorants reach the appropriate neuralstructures and induce vasodilatation, vasoconstriction and/orcerebrovascular permeability changes. Delivery of a drug can be achievedby mixing the drug with the odorant; by intravenously,intraperitoneally, or intramuscularly administering the drug, or byother delivery methods known in the art. For some applications, it isdesirable to combine a local analgesic with the odorant in order todiminish any possible sensation of pain or discomfort that may directlyor indirectly (e.g., via a reflex arc) accompany the odorant action uponnerves in the head. For example, preventing neural transmission in theneighboring pain fibers may be performed as a “pre-odorant” treatment,by topical administration of capsaicin together with a local analgesicfor several days prior to the use of odorant stimulation. In thismanner, the odorants typically induce the SPG-related response with areduced or eliminated sensation of pain or discomfort.

In general, it is believed that substantially all pharmacologicaltreatments aimed at cerebral cells for neurological and psychiatricdisorders are amenable for use with these embodiments of the presentinvention. In particular, this embodiment may be adapted for use in thetreatment of disorders such as brain tumors, epilepsy, Parkinson'sdisease, Alzheimer's disease, multiple sclerosis, schizophrenia,depression, stress, anxiety, obesity, pain, disorders requiring theadministration of various growth factors, and other CNS disorders thatare directly or indirectly affected by changes in cerebral blood flow orby BBB permeability changes.

Alternatively or additionally, a method is provided for increasing orreducing cortical blood flow and/or inducing or inhibiting vasodilation(even in the absence of BBB permeability changes) by presenting anodorant to an air passage of a patient, such as a nasal cavity or thethroat, for treatment of a condition. Patients with the aforementioneddisorders and other disorders are generally helped by vasodilation andthe resultant improvement in oxygen supply to neurons and other tissue.For some applications, this treatment is given on a long-term basis,e.g., in the chronic treatment of Alzheimer's patients. For otherapplications, the treatment is performed on a short-term basis, e.g., tominimize the damage following an acute stroke event and initiateneuronal and therefore functional rehabilitation. Alternatively oradditionally, the method provided above can be used for diagnosticpurposes or in conjunction with other diagnostic methods and/orapparatus known in the art, in order to enhance diagnostic results,reduce procedure risk, reduce procedure time, or otherwise improve suchdiagnostic procedures and/or diagnostic results. For example, methodsand apparatus described herein may be used to increase the uptake intothe brain of a radio-opaque material, in order to facilitate a CT scan.

Decreasing cerebral blood flow by presenting certain odorants to an airpassage is used in accordance with some preferred embodiments of thepresent invention to treat or prevent various types of headaches,especially with an autonomic nervous system (ANS) etiology, such asmigraine and cluster headaches.

Typically, for any of the odorant presentation applications describedherein, a suitable dosage of the odorant is determined for a desiredapplication (e.g., increasing or decreasing BBB permeability, orincreasing or decreasing cerebral blood flow). The procedure fordetermine the suitable dosage is typically performed in accordance withstandard drug dosage determination procedures known in the art, e.g.,testing a range of very small doses for safety and efficacy, andsubsequently increasing the magnitude of the doses as safety remainsacceptable and efficacy continues to increase.

In embodiments of the present invention, at least one “modulation targetsite” (MTS), as defined hereinbelow, is stimulated in order tofacilitate a diagnosis of a condition of a central nervous system (CNS)of a subject. The MTS is typically stimulated by applying electrical,chemical, mechanical and/or odorant stimulation to the site. Suchstimulation is configured to increase the permeability of theblood-brain barrier (BBB) in order to increase the transport of (a) adiagnostic agent from the systemic blood circulation of the subject intothe CNS, and/or (b) a constituent of the CNS, such as a biochemicalagent, from the CNS into the systemic circulation. The electrical,chemical, mechanical and odorant stimulation techniques described hereinmay facilitate the diagnosis of a number of CNS conditions, including,but not limited to, neurodegenerative conditions (e.g., Alzheimer'sdisease, Parkinson's Disease, and ALS), neoplastic processes (eitherprimary or metastatic), immune- and autoimmune-related disorders (e.g.,HIV and multiple sclerosis), and CNS inflammatory processes.

In the present patent application, a “modulation target site” (MTS)consists of:

-   -   a sphenopalatine ganglion (SPG) (also called a pterygopalatine        ganglion);    -   an anterior ethmoidal nerve;    -   a posterior ethmoidal nerve;    -   a communicating branch between the anterior ethmoidal nerve and        the SPG (retro-orbital branch);    -   a communicating branch between the posterior ethmoidal nerve and        the SPG (retro-orbital branch);    -   a nerve of the pterygoid canal (also called a vidian nerve),        such as a greater superficial petrosal nerve (a preganglionic        parasympathetic nerve) or a lesser deep petrosal nerve (a        postganglionic sympathetic nerve);    -   a greater palatine nerve;    -   a lesser palatine nerve;    -   a sphenopalatine nerve;    -   a communicating branch between the maxillary nerve and the        sphenopalatine ganglion;    -   a nasopalatine nerve;    -   a posterior nasal nerve;    -   an infraorbital nerve;    -   an otic ganglion;    -   an afferent fiber going into the otic ganglion; and/or    -   an efferent fiber going out of the otic ganglion.

The stimulation techniques described herein typically enhance deliveryof diagnostic and biochemical molecules across the BBB by stimulatingthe nerve fibers of the MTS, thereby inducing the middle and anteriorcerebral arteries to dilate, for example, and also causing the walls ofthese cerebral arteries to become more permeable to large molecules. Inthis manner, the movement of large molecules from within blood vesselsto the cerebral tissue, and from the cerebral issue to blood vessels, issubstantially increased. Without the use of the techniques describedherein or functional equivalents thereof, the intact BBB generallyblocks or substantially reduces the passage of such molecules.

In some embodiments of the present invention, stimulation of an MTS isconfigured to increase the transport of a diagnostic agent across theBBB from the systemic blood circulation into the CNS. Prior to, during,or after such stimulation, the diagnostic agent is administered to anon-CNS tissue of the subject, typically the systemic blood circulation,such as intravenously, and a diagnostic procedure, typically an imagingmodality, is then performed directly on the CNS. The diagnostic agent istypically a contrast agent or enhancer, or a tracer, such as aradioisotope. For example, an imaging procedure may be performed byintravenously administering labeled (e.g., radiolabeled) beta-Amyloidmonoclonal antibody (mAb) or polyclonal antibody (pAb), stimulating anMTS to transport the tracer across the BBB, and mapping the distributionof the tracer in the brain using Positron Emission Tomography (PET) orSingle Photon Emission Computed Tomography (SPECT) imaging.

These techniques for facilitating the transport of diagnostic agentsinto the CNS generally increase the accuracy of CNS diagnosticprocedures. Such increased accuracy is obtained in part because agreater amount of the agent enters the CNS as a result of the MTSstimulation. Additionally, MTS stimulation allows diagnostic agentshaving greater molecular weights to cross the BBB, which enables theeffective use of a broader range of agents having greater specificity,such as labeled antibodies and cytokines. The greater diagnosticsensitivity of these techniques also may allow the performance of anon-invasive imaging procedure instead of a more invasive procedure,such as sampling of CNS tissue or fluid (e.g., cerebrospinal fluid (CSF)lumbar puncture, brain biopsy).

In other embodiments of the present invention, stimulation of an MTS isconfigured to increase the transport of a biochemical agent across theBBB from the CNS to a non-CNS tissue of the subject, such as thesystemic blood circulation. Such biochemical agents are typicallydisease-specific biochemical markers. Prior to stimulation of an MTS toincrease BBB permeability, the concentration of such a biochemical agentis typically greater in the CNS than in the systemic circulation, i.e.,there is a concentration gradient across the endothelium. Therefore,increasing the permeability of the BBB generally releases the agent intothe systemic circulation. Once in the systemic circulation, diagnosis istypically performed by sampling a body fluid, typically blood, andanalyzing the whole blood, plasma, or serum.

These techniques for facilitating the transport of biochemical agentsfrom the CNS into the systemic circulation generally increase the rateof transfer and, consequently, the amount of the agent in the systemiccirculation. The diagnostic signal, i.e., the statistical sample size,of the agent in the circulation is thereby increased, generallyresulting in increased accuracy of the diagnostic procedure.Additionally, for some CNS conditions, use of these techniques may allowthe performance of a minimally-invasive procedure instead of a moreinvasive procedure, such as sampling of CNS tissue or fluid (e.g., CSFlumbar puncture, brain biopsy).

In some embodiments of the present invention, stimulation of at leastone MTS is achieved by presenting odorants to an air passage of apatient, such as a nasal cavity or the throat, as described herein, soas to facilitate a diagnosis of a CNS condition.

In some embodiments of the present invention, stimulation of at leastone MTS is achieved by applying a neuroexcitatory agent to the MTS.Suitable neuroexcitatory agents include, but are not limited to,acetylcholine and urocholine. For some applications, the MTS isstimulated by applying a neuroinhibitory agent, such as atropine,hexamethonium, or a local anesthetic (e.g., lidocaine).

In some embodiments of the present invention, stimulation of the MTS isachieved by applying mechanical stimulation to the MTS, e.g., vibration.

It is to be appreciated that references herein to specific modulationtarget sites are to be understood as including other modulation targetsites, as appropriate.

It is to be appreciated that, whereas preferred embodiments of thepresent invention are described with respect to driving current into theSPG or into neural structures directly related thereto, the scope of thepresent invention includes driving current into other sites in the brainwhich upon stimulation modulate cerebral blood flow or modulatepermeability properties of the BBB, as appropriate for a givenapplication.

It is also to be appreciated that electrical “stimulation,” as providedby preferred embodiments of the present invention, is meant to includesubstantially any form of current application to designated tissue, evenwhen the current is configured to block or inhibit the activity ofnerves.

It is further to be appreciated that implantation and stimulation sites,methods of implantation, and parameters of stimulation are describedherein by way of illustration and not limitation, and that the scope ofthe present invention includes other possibilities which would beobvious to someone of ordinary skill in the art who has read the presentpatent application.

It is yet further to be appreciated that while preferred embodiments ofthe invention are generally described herein with respect to electricaltransmission of power and electrical stimulation of tissue, other modesof energy transport may be used as well. Such energy includes, but isnot limited to, direct or induced electromagnetic energy, radiofrequency(RF) transmission, mechanical vibration, ultrasonic transmission,optical power, and low power laser energy (via, for example, a fiberoptic cable).

It is additionally to be appreciated that whereas preferred embodimentsof the present invention are described with respect to application ofelectrical currents to tissue, this is to be understood in the contextof the present patent application and in the claims as beingsubstantially equivalent to applying an electrical field, e.g., bycreating a voltage drop between two electrodes.

As used in the present patent application, including the claims, thecentral nervous system (CNS) is to be understood as consisting of CSF,the brain, and the spinal cord.

There is therefore provided, in accordance with a preferred embodimentof the present invention, apparatus for modifying a property of a brainof a patient, including:

-   -   one or more electrodes, adapted to be applied to a site selected        from a group of sites consisting of: a sphenopalatine ganglion        (SPG) of the patient and a neural tract originating in or        leading to the SPG; and    -   a control unit, adapted to drive the one or more electrodes to        apply a current to the site capable of inducing an increase in        permeability of a blood-brain barrier (BBB) of the patient.

There is also provided, in accordance with a preferred embodiment of thepresent invention, apparatus for modifying a property of a brain of apatient, including:

-   -   one or more electrodes, adapted to be applied to a site selected        from a group of sites consisting of: a sphenopalatine ganglion        (SPG) of the patient and a neural tract originating in or        leading to the SPG; and    -   a control unit, adapted to drive the one or more electrodes to        apply a current to the site capable of inducing an increase in        cerebral blood flow of the patient.

There is further provided, in accordance with a preferred embodiment ofthe present invention, apparatus for modifying a property of a brain ofa patient, including:

-   -   one or more electrodes, adapted to be applied to a site selected        from a group of sites consisting of: a sphenopalatine ganglion        (SPG) of the patient and a neural tract originating in or        leading to the SPG; and    -   a control unit, adapted to drive the one or more electrodes to        apply a current to the site capable of inducing a decrease in        cerebral blood flow of the patient.

There is still further provided, in accordance with a preferredembodiment of the present invention, apparatus for modifying a propertyof a brain of a patient, including:

-   -   one or more electrodes, adapted to be applied to a site selected        from a group of sites consisting of: a sphenopalatine ganglion        (SPG) of the patient and a neural tract originating in or        leading to the SPG; and    -   a control unit, adapted to drive the one or more electrodes to        apply a current to the site capable of inhibiting        parasympathetic activity of the SPG.

Preferably, the one or more electrodes are adapted for a period ofimplantation in the patient greater than about one month.

In a preferred embodiment, the apparatus includes a wire, adapted toconnect the control unit to the one or more electrodes, wherein thecontrol unit is adapted to drive the one or more electrodes from aposition external to the patient.

Alternatively or additionally, the control unit is adapted to drive theone or more electrodes by wireless communication from a positionexternal to the patient. In a preferred embodiment, the apparatusincludes an electromagnetic coupling, adapted to couple the control unitand the one or more electrodes. Alternatively or additionally, thecontrol unit is adapted to be in electro-optical communication with theone or more electrodes. Further alternatively or additionally, thecontrol unit is adapted to be in electro-acoustic communication with theone or more electrodes. Still further alternatively or additionally, thecontrol unit is adapted to be implanted in a nasal cavity of thepatient.

Preferably, the one or more electrodes are adapted to be implanted in anasal cavity of the patient. For some applications, at least one of theone or more electrodes includes a flexible electrode, adapted forinsertion through a nostril of the patient and to extend therefrom tothe site.

The apparatus preferably includes at least one biosensor, adapted tomeasure a physiological parameter of the patient and to generate asignal responsive thereto. The control unit, in turn, is preferablyadapted to modify a parameter of the applied current responsive to thesignal. As appropriate, the biosensor may include one or more of thefollowing:

-   -   a blood flow sensor.    -   a temperature sensor.    -   a chemical sensor.    -   an ultrasound sensor.    -   transcranial Doppler (TCD) apparatus.    -   laser-Doppler apparatus.    -   a systemic blood pressure sensor.    -   an intracranial blood pressure sensor.    -   a detecting element adapted to be fixed to a cerebral blood        vessel, and wherein the control unit is adapted to analyze the        signal to detect an indication of a change in blood pressure        indicative of a clot.    -   a kinetics sensor (in this case, the control unit is typically        adapted to analyze the signal to detect an indication of a        change in body disposition of the patient).    -   an electroencephalographic (EEG) sensor.    -   a blood vessel clot detector.

In a preferred embodiment, the control unit is adapted to configure thecurrent so as to facilitate uptake of a drug through the BBB when thepermeability of the BBB is increased.

Alternatively or additionally, the control unit is adapted to configurethe current so as to increase a diameter of a blood vessel and allow anembolus that is located at a site in the blood vessel to move from thesite in the blood vessel.

Further alternatively or additionally, the control unit is adapted todrive the one or more electrodes to apply the current responsive to anindication of stroke.

Still further alternatively or additionally, the control unit is adaptedto drive the one or more electrodes to apply the current responsive toan indication of migraine of the patient.

There is also provided, in accordance with a preferred embodiment of thepresent invention, a method for modifying a property of a brain of apatient, including:

-   -   selecting a site from a group of sites consisting of: a        sphenopalatine ganglion (SPG) of the patient and a neural tract        originating in or leading to the SPG; and    -   applying a current to the site capable of inducing an increase        in permeability of a blood-brain barrier (BBB) of the patient.

There is additionally provided, in accordance with a preferredembodiment of the present invention, a method for modifying a propertyof a brain of a patient, including:

-   -   selecting a site from a group of sites consisting of: a        sphenopalatine ganglion (SPG) of the patient and a neural tract        originating in or leading to the SPG; and    -   applying a current to the site capable of inducing an increase        in cerebral blood flow of the patient.

There is yet additionally provided, in accordance with a preferredembodiment of the present invention, a method for modifying a propertyof a brain of a patient, including:

-   -   selecting a site from a group of sites consisting of: a        sphenopalatine ganglion (SPG) of the patient and a neural tract        originating in or leading to the SPG; and    -   applying a current to the site capable of inducing a decrease in        cerebral blood flow of the patient.

There is still additionally provided, in accordance with a preferredembodiment of the present invention, a method for modifying a propertyof a brain of a patient, including:

-   -   selecting a site from a group of sites consisting of: a        sphenopalatine ganglion (SPG) of the patient and a neural tract        originating in or leading to the SPG; and    -   applying a current to the site capable of inhibiting        parasympathetic activity of the SPG.

For some applications, the one or more electrodes are adapted for aperiod of implantation in the patient less than about one week.

There is further provided, in accordance with a preferred embodiment ofthe present invention, vascular apparatus, including:

-   -   a detecting element, adapted to be fixed to a blood vessel of a        patient and to generate a signal responsive to energy coming        from the blood vessel; and    -   a control unit, adapted to analyze the signal so as to determine        an indication of an embolus in the blood vessel.

Preferably, the detecting element includes an energy transmitter and anenergy receiver. For example, the energy transmitter may include anultrasound transmitter or a transmitter of electromagnetic energy.

There is yet further provided, in accordance with a preferred embodimentof the present invention, a method for detecting, including:

-   -   fixing a detecting element to a blood vessel of a patient;    -   generate a signal responsive to energy coming from the blood        vessel; and    -   analyzing the signal so as to determine an indication of an        embolus in the blood vessel.

There is still further provided, in accordance with a preferredembodiment of the present invention, a method for modifying a propertyof a brain of a patient, including presenting an odorant to an airpassage of the patient, the odorant having been selected forpresentation to the air passage because it is such as to increaseconductance of molecules between a systemic blood circulation of thepatient and brain tissue of the patient, by way of a blood brain barrier(BBB) of the brain.

For some applications, the method includes sensing a parameter of thepatient and presenting the odorant responsive thereto. The parameter mayinclude an indication of a behavior of the patient, in which casesensing the parameter includes sensing the indication of the behavior ofthe patient. Alternatively, the parameter may be selected from the listconsisting of: a biochemical value of the patient and a physiologicalvalue of the patient, in which case sensing the parameter includessensing the parameter selected from the list. For some applications,sensing the parameter selected from the list includes sensing theparameter using a modality selected from the list consisting of: CT,MRI, PET, SPECT, angiography, ophthalmoscopy, fluoroscopy, lightmicroscopy, and oximetry. Alternatively or additionally, sensing theparameter selected from the list includes measuring a level of themolecules in the patient. For some applications, measuring the level ofthe molecules includes sampling a body fluid of the patient selectedfrom the list consisting of: blood, plasma, serum, ascites fluid, andurine.

In an embodiment of the present invention, presenting the odorant to theair passage of the patient includes presenting the odorant, the odoranthaving been selected for presentation to the air passage because it issuch as to increase conductance of the molecules from the systemic bloodcirculation of the patient through the blood brain barrier (BBB) intobrain tissue of the patient, the molecules being selected from the groupconsisting of: an endogenous agent, a pharmacological agent, atherapeutic agent, and an agent for facilitating a diagnostic procedure.

In an embodiment, presenting the odorant includes presenting the odorantin a dosage determined to increase the conductance of the molecules. Inan embodiment, the method includes administering the molecules forinhalation by the patient.

In an embodiment, the method includes administering the molecules to thepatient in a bolus. In an embodiment, the method includes administeringthe molecules to the patient in a generally continuous manner.

In an embodiment, the method includes administering an agent capable ofblocking a P-glycoprotein transporter from transporting the moleculesfrom a target site in the brain tissue.

In an embodiment, the method includes administering the molecules to thesystemic blood circulation. For some applications, administering themolecules includes administering the molecules mixed with the odorant.Alternatively or additionally, administering the molecules includesadministering the molecules to the systemic blood circulation using atechnique selected from the list consisting of: per-oral administrationintravenous administration, intra-arterial administration,intraperitoneal administration, subcutaneous administration, andintramuscular administration.

In an embodiment, the molecules include the agent for facilitating adiagnostic procedure, and presenting the odorant includes presenting theodorant, the odorant being such as to increase the conductance of theagent for facilitating the diagnostic procedure. For some applications,the agent for facilitating a diagnostic procedure includes an imagingcontrast agent, and presenting the odorant includes presenting theodorant, the odorant being such as to increase the conductance of theimaging contrast agent. Alternatively or additionally, the agent forfacilitating a diagnostic procedure includes a radio-opaque material,and presenting the odorant includes presenting the odorant, the odorantbeing such as to increase the conductance of the radio-opaque material.Further alternatively or additionally, the agent for facilitating adiagnostic procedure includes an antibody, and presenting the odorantincludes presenting the odorant, the odorant being such as to increasethe conductance of the antibody.

In an embodiment, presenting the odorant includes selecting themolecules, the molecules being appropriate for treating a disorder ofthe central nervous system (CNS) of the patient. In an embodiment, theCNS disorder is selected from the list consisting of: a brain tumor,epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis,schizophrenia, depression, stress, obesity, pain, and anxiety, andselecting the molecules includes selecting the molecules, the moleculesbeing appropriate for treating the selected CNS disorder.

In an embodiment, the method includes regulating a parameter of theodorant presentation. For some applications, regulating the parameterincludes regulating a parameter selected from the list consisting of:relative concentrations of two or more ingredients of the odorant, aquantity of the odorant presented, a rate of presentation of theodorant, a pressure of the odorant at presentation, and a temperature ofat least a portion of the odorant. In an embodiment, the method includesadministering the molecules to the patient during a treatment sessionthat is subsequent to regulating the parameter of the odorantpresentation. In an embodiment, the method includes administering themolecules to the patient during a treatment session, and regulating theparameter of the odorant presentation during the same treatment session.For some applications, regulating the parameter of the odorantpresentation includes selecting the parameter from a predefined set ofparameters for the odorant presentation.

For some applications, the method includes sensing a parameter of thepatient and regulating the parameter of the odorant presentationresponsive thereto. The parameter of the patient may include anindication of a behavior of the patient, in which case sensing theparameter of the patient includes sensing the indication of the behaviorof the patient Alternatively, the parameter of the patient may beselected from the list consisting of: a biochemical value of the patientand a physiological value of the patient, in which case sensing theparameter of the patient includes sensing the parameter of the patientselected from the list.

In an embodiment, the molecules include the therapeutic agent, andpresenting the odorant includes presenting the odorant, the odorantbeing such as to increase the conductance of the therapeutic agent. Forsome applications, the therapeutic agent includes a neurological drug,and presenting the odorant includes presenting the odorant, the odorantbeing such as to increase the conductance of the neurological drug. Forsome applications, the therapeutic agent includes a protein, andpresenting the odorant includes presenting the odorant, the odorantbeing such as to increase the conductance of the protein. For someapplications, the therapeutic agent includes a polymer, and presentingthe odorant includes presenting the odorant, the odorant being such asto increase the conductance of the polymer. For some applications, thetherapeutic agent includes a viral vector, and presenting the odorantincludes presenting the odorant, the odorant being such as to increasethe conductance of the viral vector.

For some applications, the therapeutic agent includes an anti-cancerdrug, and presenting the odorant includes presenting the odorant, theodorant being such as to increase the conductance of the anti-cancerdrug. For some applications, the therapeutic agent includes an agentfrom the list consisting of: glatiramer acetate and interferon beta-1b,and presenting the odorant includes presenting the odorant, the odorantbeing such as to increase the conductance of the agent selected from thelist. For some applications, the therapeutic agent includes an agentfrom the list consisting of: an agent for DNA therapy and an agent forRNA therapy, and presenting the odorant includes presenting the odorant,the odorant being such as to increase the conductance of the agentselected from the list. For some applications, the therapeutic agentincludes an agent from the list consisting of:

-   -   (a) an antisense molecule against type-1 insulin-like growth        factor receptor, and (b) ADV-HSV-tk, and presenting the odorant        includes presenting the odorant, the odorant being such as to        increase the conductance of the agent selected from the list        consisting of the antisense molecule and the ADV-HSV-tk.

In an embodiment, the method includes administering the molecules inconjunction with presenting the odorant. In an embodiment, administeringthe molecules in conjunction with presenting the odorant includesadministering the molecules at a time determined with respect to a timeof presenting the odorant. For some applications, administering themolecules includes administering the molecules at least a predeterminedtime prior to presenting the odorant. Alternatively, administering themolecules includes administering the molecules at generally the sametime as presenting the odorant. Further alternatively, administering themolecules includes administering the molecules at least a predeterminedtime subsequent to presenting the odorant.

In an embodiment, the molecules include the pharmacological agent, andpresenting the odorant includes presenting the odorant, the odorantbeing such as to increase the conductance of the pharmacological agent.For some applications, the pharmacological agent includes a viralvector, and presenting the odorant includes presenting the odorant, theodorant being such as to increase the conductance of the viral vector.For some applications, the pharmacological agent includes an antibody,and presenting the odorant includes presenting the odorant, the odorantbeing such as to increase the conductance of the antibody. For someapplications, the antibody is selected from the list consisting of: atoxin-antibody complex, a radiolabeled antibody, and anti-HER2 mAb, andpresenting the odorant includes presenting the odorant, the odorantbeing such as to increase the conductance of the selected antibody.Alternatively, the antibody is selected from the list consisting of:anti-b-amyloid antibody and anti-amyloid-precursor-protein antibody, andpresenting the odorant includes presenting the odorant, the odorantbeing such as to increase the conductance of the selected antibody.

In an embodiment, the molecules include the endogenous agent, andpresenting the odorant includes presenting the odorant, the odorantbeing such as to increase the conductance of the endogenous agent. Forsome applications, the endogenous agent includes an endogenous agentsubstantially unmodified by artificial means, and presenting the odorantincludes presenting the odorant, the odorant being such as to increasethe conductance of the endogenous agent that is substantially unmodifiedby artificial means. Alternatively, the endogenous agent includes anendogenous agent an aspect of which is modified by artificial means, andpresenting the odorant includes presenting the odorant, the odorantbeing such as to increase the conductance of the endogenous agent theaspect of which is modified by artificial means. Further alternatively,the endogenous agent includes an enzyme, and presenting the odorantincludes presenting the odorant, the odorant being such as to increasethe conductance of the enzyme. For some applications, the enzymeincludes hexosamimidase, and presenting the odorant includes presentingthe odorant, the odorant being such as to increase the conductance ofthe hexosaminidase.

In an embodiment, the method includes administering the molecules to amucous membrane of the patient. For some applications, administering themolecules includes administering the molecules to oral mucosa of thepatient. Alternatively, administering the molecules includesadministering the molecules to nasal mucosa of the patient.

For some applications, administering the molecules includesadministering the molecules in combination with the odorant.Alternatively, administering the molecules includes administering themolecules separately from the odorant.

In an embodiment of the present invention, presenting the odorant to theair passage of the patient includes presenting the odorant, the odoranthaving been selected for presentation to the air passage because it issuch as to increase conductance of molecules from the brain tissue ofthe patient through the blood brain barrier (BBB) into the systemicblood circulation.

In an embodiment, the method includes sensing a quantity of themolecules from a site outside of the brain of the patient, followinginitiation of presentation of the odorant. For some applications,sensing the quantity of the molecules includes sensing using a modalityselected from the list consisting of: CT, MRI, PET, SPECT, angiography,ophthalmoscopy, fluoroscopy, light microscopy, and oximetry. For someapplications, sensing the quantity of the molecules includes sampling afluid of the patient selected from the list consisting of: blood,plasma, serum, ascites fluid, and urine.

In an embodiment, the method includes determining adiagnostically-relevant parameter responsive to sensing the quantity ofthe molecules.

In an embodiment, the method includes selecting a dosage of the odorantresponsive to a disorder of the patient. For some applications,selecting the dosage of the odorant includes determining a dosage of theodorant that increases conductance of the molecules, responsive topresentation of the odorant, to an extent sufficient to treat thedisorder at least in part. For some applications, selecting the dosageincludes selecting the dosage responsive to the disorder of the patient,the disorder being selected from the list consisting of: a brain tumor,epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis,schizophrenia, depression, stress, obesity, pain, and anxiety.

In an embodiment, the method includes administering ahyperosmolarity-inducing agent to the patient at a dosage sufficient toaugment an increase in conductance of the molecules caused bypresentation of the odorant.

In an embodiment, the method includes inducing a state of dehydration ofthe patient, of an extent sufficient to augment an increase inconductance of the molecules caused by presentation of the odorant.

In an embodiment, the method includes administering an agent to thepatient that modulates synthesis or metabolism of nitric-oxide (NO) inblood vessels of the brain, at a dosage sufficient to augment anincrease in conductance of the molecules caused by presentation of theodorant.

There is additionally provided, in accordance with a preferredembodiment of the present invention, a method for modifying a propertyof a brain of a patient during or following a stroke event, includingpresenting an odorant to an air passage of the patient, the odoranthaving been selected for presentation to the air passage because it iscapable of inducing an increase in cerebral blood flow of the patient,so as to reduce a pathology associated with the stroke event.

In an embodiment, presenting the odorant includes presenting the odorantin a dosage determined to increase the cerebral blood flow.

There is also provided, in accordance with a preferred embodiment of thepresent invention, a method for modifying a property of a brain of apatient who suffers from headache attacks, including presenting anodorant to an air passage of the patient, the odorant having beenselected for presentation to the air passage because it is capable ofmodifying cerebral blood flow of the patient, so as to reduce a severityof a headache attack of the patient.

In an embodiment, presenting the odorant includes presenting the odorantin a dosage determined to modify the cerebral blood flow.

In an embodiment, presenting the odorant includes selecting the odorant,the odorant being capable of decreasing the cerebral blood flow, so asto reduce the severity of the headache attack.

In an embodiment, the headache attack includes a migraine headacheattack of the patient, and presenting the odorant includes presenting tothe air passage an odorant that is capable of reducing the cerebralblood flow, so as to reduce the severity of the migraine headacheattack. In an embodiment, the headache attack includes a clusterheadache attack of the patient, and presenting the odorant includespresenting to the air passage an odorant that is capable of reducing thecerebral blood flow, so as to reduce the severity of the clusterheadache attack.

There is further provided, in accordance with a preferred embodiment ofthe present invention, a method for modifying a property of a brain of apatient who suffers from a disorder of the central nervous system (CNS),including presenting an odorant to an air passage of the patient, theodorant having been selected for presentation to the air passage becauseit is capable of modifying cerebral blood flow of the patient, so as totreat the CNS disorder.

In an embodiment, presenting the odorant includes presenting the odorantin a dosage determined to modify the cerebral blood flow.

In an embodiment, the CNS disorder is selected from the list consistingof: a brain tumor, epilepsy, Parkinson's disease, Alzheimer's disease,multiple sclerosis, schizophrenia, depression, stress, obesity, pain,and anxiety, and presenting the odorant includes presenting the odorantthat is capable of modifying the cerebral blood flow, so as to treat theselected CNS disorder.

In an embodiment, presenting the odorant includes selecting the odorant,the odorant being capable of decreasing the cerebral blood flow. In anembodiment, presenting the odorant includes selecting the odorant, theodorant being capable of increasing cerebral blood flow of the patient.In an embodiment, presenting the odorant includes selecting the odorant,the odorant being capable of increasing cortical blood flow of thepatient.

There is still further provided, in accordance with a preferredembodiment of the present invention, a method for modifying a propertyof a brain of a patient, including presenting an odorant to an airpassage of the patient, the odorant having been selected forpresentation to the air passage because it is such as to decreaseconductance of molecules from a systemic blood circulation of thepatient through a blood brain barrier (BBB) of the brain into braintissue of the patient.

In an embodiment, presenting the odorant includes presenting the odorantin a dosage determined to decrease the conductance of the molecules.

In an embodiment, the method includes presenting in association with theodorant an analgesic in a dosage configured to reduce a sensationassociated with the presenting of the odorant. In an embodiment,presenting the analgesic includes topically presenting the analgesic ata site selected from the list consisting of: a vicinity of one or morenerves in a nasal cavity of the patient, a vicinity of one or morenerves in an oral cavity of the patient, and a vicinity of one or morenerves innervating a face of the patient. In an embodiment, presentingthe analgesic includes topically presenting the analgesic in a vicinityof a sphenopalatine ganglion (SPG) of the patient. In an embodiment,presenting the analgesic includes administering the analgesic forinhalation at generally the same time as the presenting of the odorant.

In an embodiment, the air passage includes a nasal cavity of thepatient, and presenting the odorant includes presenting the odorant tothe nasal cavity.

In an embodiment, the air passage includes a throat of the patient, andpresenting the odorant includes presenting the odorant to the throat.

In an embodiment, the odorant is selected from the list consisting of:propionic acid, cyclohexanone, and amyl acetate, and presenting theodorant includes presenting the selected odorant. Alternatively, theodorant is selected from the list consisting of: acetic acid, citricacid, carbon dioxide, sodium chloride, and ammonia, and presenting theodorant includes presenting the selected odorant. Further alternatively,the odorant is selected from the list consisting of: menthol, alcohol,nicotine, piperine, gingerol, zingerone, allyl isothiocyanate,cinnamaldehyde, cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate,thymol, and eucalyptol, and presenting the odorant includes presentingthe selected odorant.

In an embodiment, presenting the odorant includes presenting a capsulefor placement within a mouth of the patient, the capsule beingconfigured to dissolve upon contact with salivary liquids of thepatient, whereupon the odorant is presented to the air passage.

In an embodiment, the method includes regulating a parameter of theodorant presentation. For some applications, regulating the parameterincludes regulating a parameter selected from the list consisting of:relative concentrations of two or more ingredients of the odorant, aquantity of the odorant presented, a rate of presentation of theodorant, a pressure of the odorant at presentation, and a temperature ofat least a portion of the odorant. Alternatively or additionally,regulating the parameter of the odorant presentation includes selectingthe parameter from a predefined set of parameters for the odorantpresentation.

In an embodiment, the method includes sensing a parameter of the patientand regulating the parameter of the odorant presentation responsivethereto. For some applications, the parameter of the patient includes anindication of a behavior of the patient, and sensing the parameter ofthe patient includes sensing the indication of the behavior of thepatient.

In an embodiment, the parameter of the patient is selected from the listconsisting of: a biochemical value of the patient and a physiologicalvalue of the patient, and sensing the parameter of the patient includessensing the parameter of the patient selected from the list.

In an embodiment, the method includes sensing a parameter of the patientand presenting the odorant responsive thereto. For some applications,the parameter includes an indication of a behavior of the patient, andsensing the parameter includes sensing the indication of the behavior ofthe patient. Alternatively, the parameter is selected from the listconsisting of: a biochemical value of the patient and a physiologicalvalue of the patient, and sensing the parameter includes sensing theparameter selected from the list. For some applications, sensing theparameter selected from the list includes sensing the parameter using amodality selected from the list consisting of: CT, MRI, PET, SPECT,angiography, ophthalmoscopy, fluoroscopy, light microscopy, andoximetry. Alternatively, sensing the parameter selected from the listincludes sampling a body fluid of the patient selected from the listconsisting of: blood, plasma, serum, ascites fluid, and urine.

There is additionally provided, in accordance with a preferredembodiment of the present invention, apparatus for modifying a propertyof a brain of a patient, including:

-   -   an odorant-storage vessel;    -   an odorant for storage within the odorant-storage vessel, the        odorant being capable of increasing conductance of molecules        from a systemic blood circulation of the patient through a blood        brain barrier (BBB) of the brain into brain tissue of the        patient, the molecules being selected from the group consisting        of: a pharmacological agent, a therapeutic agent, and an agent        for facilitating a diagnostic procedure; and    -   an odorant-delivery element, adapted to present the odorant to        an air passage of the patient.

In an embodiment, the odorant-storage vessel is adapted to store theodorant mixed with the molecules.

In an embodiment, the molecules include the therapeutic agent, and theodorant is such as to increase the conductance of the therapeutic agent.

In an embodiment, the therapeutic agent includes a neurological drug,and the odorant is such as to increase the conductance of theneurological drug.

In an embodiment, the molecules include the agent for facilitating adiagnostic procedure, and the odorant is such as to increase theconductance of the agent for facilitating the diagnostic procedure. Forsome applications, the agent for facilitating a diagnostic procedureincludes a radio-opaque material, and the odorant is such as to increasethe conductance of the radio-opaque material.

In an embodiment, the odorant includes an agent for facilitatingtreatment of a disorder of the central nervous system (CNS) of thepatient. For some applications, the CNS disorder is selected from thelist consisting of: a brain tumor, epilepsy, Parkinson's disease,Alzheimer's disease, multiple sclerosis, schizophrenia, depression,stress, obesity, pain, and anxiety, and the odorant includes an agentfor facilitating treatment of the selected CNS disorder.

There is yet additionally provided, in accordance with a preferredembodiment of the present invention, apparatus for modifying a propertyof a brain of a patient during or following a stroke event, including:

-   -   an odorant-storage vessel;    -   an odorant, for storage within the odorant-storage vessel, the        odorant being capable of inducing an increase in cerebral blood        flow of the patient; and    -   an odorant-delivery element, adapted to present the odorant to        an air passage of the patient, so as to reduce a pathology        associated with the stroke event.

There is further provided, in accordance with a preferred embodiment ofthe present invention, apparatus for modifying a property of a brain ofa patient who suffers from headache attacks, including:

-   -   an odorant-storage vessel;    -   an odorant, for storage within the odorant-storage vessel, the        odorant being capable of modifying cerebral blood flow of the        patient; and    -   an odorant-delivery element, configured to present the odorant        to an air passage of the patient, so as to reduce a severity of        a headache attack of the patient.

In an embodiment, the odorant is capable of decreasing the cerebralblood flow.

In an embodiment, the headache attack includes a migraine headacheattack of the patient, and the odorant is capable of reducing theseverity of the migraine headache attack. In an embodiment, the headacheattack includes a cluster headache attack of the patient, and theodorant is capable of reducing the severity of the cluster headacheattack.

There is still additionally provided, in accordance with a preferredembodiment of the present invention, apparatus for modifying a propertyof a brain of a patient who suffers from a disorder of the centralnervous system (CNS), including:

-   -   an odorant-storage vessel;    -   an odorant for storage within the odorant-storage vessel, the        odorant being capable of modifying cerebral blood flow of the        patient; and    -   an odorant-delivery element, configured to present the odorant        to an air passage of the patient, so as to treat the CNS        disorder.

In an embodiment, the CNS disorder is selected from the list consistingof: a brain tumor, epilepsy, Parkinson's disease, Alzheimer's disease,multiple sclerosis, schizophrenia, depression, stress, obesity, pain,and anxiety, and the odorant includes an agent for facilitatingtreatment of the selected CNS disorder.

In an embodiment, the odorant is capable of decreasing the cerebralblood flow. Alternatively, the odorant is capable of increasing thecerebral blood flow. For some applications, the odorant is capable ofincreasing cortical blood flow of the patient.

There is further provided, in accordance with a preferred embodiment ofthe present invention, apparatus for modifying a property of a brain ofa patient, including:

-   -   an odorant-storage vessel;    -   an odorant, for storage within the odorant-storage vessel, the        odorant being capable of decreasing conductance of molecules        from a systemic blood circulation of the patient through a blood        brain barrier (BBB) of the brain into brain tissue of the        patient; and    -   an odorant-delivery element, adapted to present the odorant to        an air passage of the patient.

In an embodiment, the apparatus includes an analgesic for storage withinthe odorant-storage vessel in a dosage configured to reduce a sensationassociated with the presenting of the odorant, and the odorant-deliveryelement is adapted to present the analgesic to the air passage inassociation with the odorant.

In an embodiment, the odorant-storage vessel in combination with theodorant-delivery element includes an aqueous spray nasal inhaler.Alternatively, the odorant-storage vessel in combination with theodorant-delivery element includes a metered dose nasal inhaler. Furtheralternatively, the odorant-storage vessel in combination with theodorant-delivery element includes an air-dilution olfactometer.

In an embodiment, the air passage includes a nasal cavity of thepatient, and the odorant-delivery element is adapted to present theodorant to the nasal cavity.

In an embodiment, the air passage includes a throat of the patient, andthe odorant-delivery element is adapted to present the odorant to thethroat.

In an embodiment, the odorant includes an agent selected from the listconsisting of: propionic acid, cyclohexanone, and amyl acetate.Alternatively, the odorant includes an agent selected from the listconsisting of: acetic acid, citric acid, carbon dioxide, sodiumchloride, and ammonia. Further alternatively, the odorant includes anagent selected from the list consisting of: menthol, alcohol, nicotine,piperine, gingerol, zingerone, allyl isothiocyanate, cinnamaldehyde,cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate, thymol, andeucalyptol.

In an embodiment, the odorant-storage vessel includes a capsule forplacement in a mouth of the patient, and the odorant-delivery elementincludes a portion of the capsule adapted to dissolve upon contact withsalivary liquids of the patient, whereupon the odorant is presented tothe air passage of the patient.

There is also provided, in accordance with a preferred embodiment of thepresent invention, a method for treating Alzheimer's disease (AD),including stimulating a sphenopalatine ganglion (SPG) of a subject sothat the concentration of a substance in a brain of the subject changes.

In a preferred embodiment, the stimulation causes increased clearance ofthe substance from the brain. As appropriate, the substance may be oneor more of the following:

-   -   amyloid;    -   tau protein;    -   PS1;    -   PS2;    -   RNA fragments;    -   cytokine;    -   a marker of neuronal death;    -   a marker of neuronal degeneration;    -   a marker of an inflammatory process; and    -   a neurotoxic substance.

Alternatively or additionally, the substance may include DNA.

In another preferred embodiment, the stimulation causes increasedclearance of the substance from cerebrospinal fluid (CSF). Asappropriate, the substance may be one or more of the following:

-   -   amyloid;    -   tau protein;    -   PS1;    -   PS2;    -   RNA fragments;    -   cytokine;    -   a marker of neuronal death;    -   a marker of neuronal degeneration;    -   a marker of an inflammatory process; and    -   a neurotoxic substance.

Alternatively or additionally, the substance may include DNA.

There is additionally provided, in accordance with a preferredembodiment of the present invention, a method for treating Alzheimer'sdisease (AD), including:

-   -   supplying a pharmaceutical agent to blood of a subject; and    -   stimulating a sphenopalatine ganglion (SPG) of the subject so        that the concentration of the pharmaceutical agent in a brain of        the subject increases.

As appropriate, the pharmaceutical agent may be one or more of thefollowing:

-   -   a glutamate receptor antagonist;    -   a β-amyloid inhibitor;    -   an NMDA-receptor blocker;    -   a combination of an AD vaccine and an anti-inflammatory drug;    -   a microglial activation modulator;    -   a cholinesterase inhibitor;    -   a stimulant of nerve regeneration;    -   a nerve growth factor;    -   a compound that stimulates production of nerve growth factor;    -   an antioxidant;    -   a hormone;    -   an inhibitor of protein tyrosine phosphatases;    -   medium chain triglycerides;    -   an endogenous protein;    -   a gene therapy agent;    -   an anti-inflammatory drug;    -   a non-steroidal anti-inflammatory drug; and    -   an AD vaccine. More specifically, the AD vaccine may contain        antibodies against a specific protein that is characteristic of        AD. Still more specifically, the AD vaccine may contain        antibodies against P-amyloid and/or antibodies against tau        protein.

Alternatively, the pharmaceutical agent is adapted to have an inhibitoryeffect on the derivation of β-amyloid from amyloid precursor protein.

There is yet additionally provided, in accordance with a preferredembodiment of the present invention, a method for diagnosing Alzheimer'sdisease (AD), including stimulating a sphenopalatine ganglion (SPG) of asubject so that molecular passage increases between a central nervoussystem (CNS) of the subject and another body compartment of the subject.

Preferably, the method includes measuring a constituent of the otherbody compartment. As appropriate, the other body compartment may be oneof the following:

-   -   blood of the subject;    -   plasma of the subject;    -   serum of the subject; and    -   ascites of the subject.

There is still additionally provided, in accordance with a preferredembodiment of the present invention, a method for diagnosing Alzheimer'sdisease (AD), including stimulating a sphenopalatine ganglion (SPG) of asubject so that molecular passage increases between cerebrospinal fluid(CSF) of the subject and another body fluid of the subject.

Preferably, the method includes measuring a constituent of the otherbody fluid. More preferably, the method includes correlating an abnormalconcentration of the constituent to a pathology of AD. As appropriate,the constituent may be selected from the group consisting of thefollowing: a protein, a hormone, an antibody, an electrolyte, aneuropeptide, and an enzyme.

Alternatively or additionally, the measurement is performed by samplinga fluid selected from the group consisting of the following: wholeblood, plasma, serum, and ascites. Further alternatively oradditionally, the measurement is performed by extracting the fluid fromtissue of the subject.

Optionally, the measurement may be performed by measuring more than oneconstituent. In this case, a diagnostic result may be determinedaccording to the interrelation between concentrations of theconstituents.

There is also provided, in accordance with a preferred embodiment of thepresent invention, a method for diagnosing Alzheimer's disease (AD),including stimulating a sphenopalatine ganglion (SPG) of a subject sothat molecular passage increases between cerebrospinal fluid (CSF) ofthe subject and a tissue of the subject.

Preferably, the method includes measuring a constituent of the tissue.More preferably, the method includes correlating an abnormalconcentration of the constituent to a pathology of AD. As appropriate,the constituent may be selected from the group consisting of thefollowing: a protein, a hormone, an antibody, an electrolyte, aneuropeptide, and an enzyme.

Optionally, the measurement may be performed by measuring more than oneconstituent. In this case, a diagnostic result may be determinedaccording to the interrelation between concentrations of theconstituents.

There is further provided, in accordance with a preferred embodiment ofthe present invention, a system for treating Alzheimer's disease (AD),including a stimulator for stimulating the sphenopalatine ganglion (SPG)of a subject, so that the concentration of a substance in a brain of thesubject changes.

There is yet further provided, in accordance with a preferred embodimentof the present invention, a pharmaceutical agent delivery system fortreating Alzheimer's disease (AD), including:

-   -   a pharmaceutical agent supplied to a body of a subject for        delivery to a brain of the subject via blood of said subject;        and    -   a stimulator for stimulating a sphenopalatine ganglion (SPG) of        the subject, so that the concentration of the pharmaceutical        agent in the brain increases.

There is still further provided, in accordance with a preferredembodiment of the present invention, a system for diagnosing Alzheimer'sdisease (AD), including a stimulator for stimulating a sphenopalatineganglion (SPG) of a subject, so that molecular passage increases betweena CNS of the subject and another body compartment of the subject.

There is additionally provided, in accordance with a preferredembodiment of the present invention, a system for diagnosing Alzheimer'sdisease (AD), including a stimulator for stimulating a sphenopalatineganglion (SPG) of a subject, so that molecular passage increases betweencerebrospinal fluid (CSF) of the subject and another body fluid of thesubject.

There is yet additionally provided, in accordance with a preferredembodiment of the present invention, a system for diagnosing Alzheimer'sdisease (AD), including a stimulator for stimulating a sphenopalatineganglion (SPG) of a subject, so that molecular passage increases betweencerebrospinal fluid (CSF) of the subject and a tissue of the subject.

There is therefore provided, in accordance with an embodiment of thepresent invention, a method for treating Alzheimer's disease (AD),including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of a        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        clearance of an AD-related constituent of a central nervous        system (CNS) of the subject, from a brain of the subject to a        systemic blood circulation of the subject, so as to treat the        AD.

There is further provided, in accordance with an embodiment of thepresent invention, a method for treating Alzheimer's disease (AD),including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of a        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        clearance of an AD-related constituent of a central nervous        system (CNS) of the subject, from a brain of the subject to a        systemic blood circulation of the subject, so as to treat the        AD.

There is still further provided, in accordance with an embodiment of thepresent invention, a method for treating Alzheimer's disease (AD),including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of a        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        clearance of an AD-related constituent of a central nervous        system (CNS) of the subject, from cerebrospinal fluid (CSF) of        the subject to a systemic blood circulation of the subject, so        as to treat the AD.

There is yet further provided, in accordance with an embodiment of thepresent invention, a method for treating Alzheimer's disease (AD),including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of a        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        clearance of an AD-related constituent of a central nervous        system (CNS) of the subject, from cerebrospinal fluid (CSF) of        the subject to a systemic blood circulation of the subject, so        as to treat the AD.

In an embodiment, stimulating the SPG-related tissue includes directlystimulating the SPG.

For some applications, the AD-related constituent includes aninflammatory-related constituent, tau protein, PS1, PS2, a DNA fragment,an RNA fragment, a cytokine, a marker of neuronal death or degeneration,a marker of an inflammatory process, a neurotoxic substance, amyloidprotein, an amyloid protein selected from the list consisting of: wildamyloid protein and mutated amyloid protein, and/or an amyloid proteinselected from the list consisting of: fragmented amyloid protein andwhole amyloid protein, and configuring the stimulation includesconfiguring the stimulation so as to cause the increase in the clearanceof the inflammatory-related constituent, tau protein, PS1, PS2, DNAfragment, RNA fragment, cytokine, marker of neuronal death ordegeneration, marker of an inflammatory process, neurotoxic substance,amyloid protein, amyloid protein selected from the list consisting of:wild amyloid protein and mutated amyloid protein, and/or amyloid proteinselected from the list consisting of: fragmented amyloid protein andwhole amyloid protein.

There is also provided, in accordance with an embodiment of the presentinvention, a method for treating Alzheimer's disease (AD), including:

-   -   supplying a pharmaceutical agent to a systemic blood circulation        of a subject;    -   stimulating sphenopalatine ganglion (SPG)-related tissue of the        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        passage of the pharmaceutical agent from the systemic blood        circulation into a central nervous system (CNS) of the subject,        so as to treat the AD.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method for treating Alzheimer's disease (AD),including:

-   -   supplying a pharmaceutical agent to a systemic blood circulation        of a subject;    -   stimulating sphenopalatine ganglion (SPG)-related tissue of the        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        passage of the pharmaceutical agent from the systemic blood        circulation into a central nervous system (CNS) of the subject,        so as to treat the AD.

In an embodiment, supplying the pharmaceutical agent includesadministering the pharmaceutical agent to the systemic blood circulationusing a technique selected from the list consisting of: per-oraladministration, intravenous administration, intra-arterialadministration, intraperitoneal administration, subcutaneousadministration, and intramuscular administration.

For some applications, the pharmaceutical agent includes a glutamatereceptor antagonist, an NMDA receptor blocker, an agent having aninhibitory effect on derivation of β-amyloid from amyloid precursorprotein, a cholinesterase inhibitor, a stimulant of nerve regeneration,a nerve growth factor, a compound that stimulates production of nervegrowth factor, a microglial activation modulator, an antioxidant, ahormone, an inhibitor of protein tyrosine phosphatases, a medium chaintriglyceride, a gene therapy agent, a β-amyloid inhibitor, an endogenousprotein, an anti-inflammatory agent, a non-steroidal anti-inflammatorydrug (NSAID), or a pharmaceutical agent selected from the listconsisting of: an AD vaccine, a component of an AD vaccine, and aderivative of an AD vaccine (for example, the selected pharmaceuticalagent including (a) an anti-inflammatory drug, (b) antibodies against aspecific protein that is characteristic of AD, (c) antibodies againstβ-amyloid, or (d) antibodies against tau protein), and configuring thestimulation includes configuring the stimulation so as to cause theincrease in the passage of the pharmaceutical agent.

In an embodiment, supplying the pharmaceutical agent includesadministering the pharmaceutical agent for inhalation by the subject.For example, administering the pharmaceutical agent for inhalation bythe subject may include administering the pharmaceutical agent mixedwith the odorant.

There is still additionally provided, in accordance with an embodimentof the present invention, a method for treating Alzheimer's disease(AD), including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of the        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        cerebral blood flow (CBF) of the subject, so as to treat the AD.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method for treating Alzheimer's disease (AD),including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of the        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        cerebral blood flow (CBF) of the subject, so as to treat the AD.

In an embodiment, configuring the stimulation includes configuring thestimulation so as to cause an improvement in a metabolic state of acentral nervous system (CNS) of the subject.

There is also provided, in accordance with an embodiment of the presentinvention, a method for diagnosing Alzheimer's disease (AD), including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of a        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        molecular passage between a central nervous system (CNS) of the        subject and another body compartment of the subject, so as to        facilitate a diagnosis of the AD.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method for diagnosing Alzheimer's disease (AD),including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of a        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        molecular passage between a central nervous system (CNS) of the        subject and another body compartment of the subject, so as to        facilitate a diagnosis of the AD.

In an embodiment, the method includes measuring a constituent of theother body compartment.

For some applications, the other body compartment includes a systemicblood circulation of the subject, and configuring the stimulationincludes configuring the stimulation so as to cause the increase inmolecular passage between the CNS and the systemic blood circulation.Alternatively or additionally, the other body compartment includesplasma of the subject, and configuring the stimulation includesconfiguring the stimulation so as to cause the increase in molecularpassage between the CNS and the plasma. Further alternatively oradditionally, the other body compartment includes serum of the subject,and configuring the stimulation includes configuring the stimulation soas to cause the increase in molecular passage between the CNS and theserum. Still further alternatively or additionally, the other bodycompartment is ascites of the subject, and configuring the stimulationincludes configuring the stimulation so as to cause the increase inmolecular passage between the CNS and the ascites.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method for diagnosing Alzheimer's disease (AD),including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of a        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        molecular passage between cerebrospinal fluid (CSF) of the        subject and another body fluid of the subject, so as to        facilitate a diagnosis of the AD.

There is still additionally provided, in accordance with an embodimentof the present invention, a method for diagnosing Alzheimer's disease(AD), including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of a        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        molecular passage between cerebrospinal fluid (CSF) of the        subject and another body fluid of the subject, so as to        facilitate a diagnosis of the AD.

In an embodiment, the method includes measuring a constituent of theother body fluid.

In an embodiment, the method includes correlating an abnormalconcentration of the constituent to a pathology of AD.

For some applications, the constituent is selected from the groupconsisting of: a protein, a hormone, an antibody, an electrolyte, aneuropeptide, and an enzyme, and measuring the constituent includesmeasuring the selected constituent. Alternatively or additionally, theother body fluid is selected from the list consisting of: whole blood,plasma, serum, and ascites, and measuring the constituent includessampling the selected fluid.

Measuring the constituent typically includes extracting the other bodyfluid from tissue of the subject, and, for some applications, measuringa plurality of constituents. In an embodiment, the method includesdetermining a diagnostic result according to the interrelation betweenconcentrations of the constituents.

There is also provided, in accordance with an embodiment of the presentinvention, a method for diagnosing Alzheimer's disease (AD), including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of a        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        molecular passage between cerebrospinal fluid (CSF) of the        subject and a tissue of the subject, so as to facilitate a        diagnosis of the AD.

There is further provided, in accordance with an embodiment of thepresent invention, a method for diagnosing Alzheimer's disease (AD),including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of a        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        molecular passage between cerebrospinal fluid (CSF) of the        subject and a tissue of the subject, so as to facilitate a        diagnosis of the AD.

For some applications, the method includes measuring a constituent ofthe tissue and/or correlating an abnormal concentration of theconstituent to a pathology of AD.

In accordance with an embodiment of the present invention, theconstituent is selected from the group consisting of: a protein, ahormone, an antibody, an electrolyte, a neuropeptide, and an enzyme, andmeasuring the constituent includes measuring the selected constituent.

In an embodiment, measuring the constituent includes measuring aplurality of constituents of the tissue. In this case, for someapplications, the method includes determining a diagnostic resultaccording to the interrelation between concentrations of theconstituents of the tissue.

There is still further provided, in accordance with an embodiment of thepresent invention, a method for treating Alzheimer's disease (AD),including:

-   -   applying an electrical signal to at least one site of a subject,        the site selected from the list consisting of: a sphenopalatine        ganglion (SPG) of the subject, an anterior ethmoidal nerve of        the subject, a posterior ethmoidal nerve of the subject, a        communicating branch between an anterior ethmoidal nerve and a        retro-orbital branch of an SPG of the subject, a communicating        branch between a posterior ethmoidal nerve and a retro-orbital        branch of an SPG of the subject, a greater palatine nerve of the        subject, a lesser palatine nerve of the subject, a        sphenopalatine nerve of the subject, a communicating branch        between a maxillary nerve and an SPG of the subject, a        nasopalatine nerve of the subject, a posterior nasal nerve of        the subject, an infraorbital nerve of the subject, an otic        ganglion of the subject, an afferent fiber going into the otic        ganglion of the subject, an efferent fiber going out of the otic        ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject; and    -   configuring the signal so as to cause an increase in clearance        of an AD-related constituent of a central nervous system (CNS)        of the subject, from a brain of the subject to a systemic blood        circulation of the subject, so as to treat the AD.

There is yet further provided, in accordance with an embodiment of thepresent invention, a method for treating Alzheimer's disease (AD),including presenting an odorant to an air passage of a subject, theodorant having been selected for presentation to the air passage becauseit is such as to cause an increase in clearance of an AD-relatedconstituent of a central nervous system (CNS) of the subject fromcerebrospinal fluid (CSF) of the subject to a systemic blood circulationof the subject, so as to treat the AD.

There is also provided, in accordance with an embodiment of the presentinvention, a method for treating Alzheimer's disease (AD), including:

-   -   supplying a pharmaceutical agent to a systemic blood circulation        of a subject;    -   applying an electrical signal to at least one site of a subject,        the site selected from the list consisting of: a sphenopalatine        ganglion (SPG) of the subject, an anterior ethmoidal nerve of        the subject, a posterior ethmoidal nerve of the subject, a        communicating branch between an anterior ethmoidal nerve and a        retro-orbital branch of an SPG of the subject, a communicating        branch between a posterior ethmoidal nerve and a retro-orbital        branch of an SPG of the subject, a greater palatine nerve of the        subject, a lesser palatine nerve of the subject, a        sphenopalatine nerve of the subject, a communicating branch        between a maxillary nerve and an SPG of the subject, a        nasopalatine nerve of the subject, a posterior nasal nerve of        the subject, an infraorbital nerve of the subject, an otic        ganglion of the subject, an afferent fiber going into the otic        ganglion of the subject, an efferent fiber going out of the otic        ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject; and    -   configuring the signal so as to cause an increase in passage of        the pharmaceutical agent from the systemic blood circulation        into a central nervous system (CNS) of the subject, so as to        treat the AD.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method for treating Alzheimer's disease (AD),including:

-   -   supplying a pharmaceutical agent to a systemic blood circulation        of a subject; and    -   presenting an odorant to an air passage of the subject, the        odorant having been selected for presentation to the air passage        because it is such as to cause an increase in passage of the        pharmaceutical agent from the systemic blood circulation into a        central nervous system (CNS) of the subject, so as to treat the        AD.

There is still additionally provided, in accordance with an embodimentof the present invention, a method for treating Alzheimer's disease(AD), including:

-   -   applying an electrical signal to at least one site of a subject,        the site selected from the list consisting of: a sphenopalatine        ganglion (SPG) of the subject, an anterior ethmoidal nerve of        the subject, a posterior ethmoidal nerve of the subject, a        communicating branch between an anterior ethmoidal nerve and a        retro-orbital branch of an SPG of the subject, a communicating        branch between a posterior ethmoidal nerve and a retro-orbital        branch of an SPG of the subject, a greater palatine nerve of the        subject, a lesser palatine nerve of the subject, a        sphenopalatine nerve of the subject, a communicating branch        between a maxillary nerve and an SPG of the subject, a        nasopalatine nerve of the subject, a posterior nasal nerve of        the subject, an infraorbital nerve of the subject, an otic        ganglion of the subject, an afferent fiber going into the otic        ganglion of the subject, an efferent fiber going out of the otic        ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject; and    -   configuring the signal so as to cause an increase in cerebral        blood flow (CBF) of the subject, so as to treat the AD.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method for treating Alzheimer's disease (AD),including presenting an odorant to an air passage of the subject, theodorant having been selected for presentation to the air passage becauseit is such as to cause an increase in cerebral blood flow (CBF) of thesubject, so as to treat the AD.

There is also provided, in accordance with an embodiment of the presentinvention, a method for diagnosing Alzheimer's disease (AD), including:

-   -   applying an electrical signal to at least one site of a subject,        the site selected from the list consisting of: a sphenopalatine        ganglion (SPG) of the subject, an anterior ethmoidal nerve of        the subject, a posterior ethmoidal nerve of the subject, a        communicating branch between an anterior ethmoidal nerve and a        retro-orbital branch of an SPG of the subject, a communicating        branch between a posterior ethmoidal nerve and a retro-orbital        branch of an SPG of the subject, a greater palatine nerve of the        subject, a lesser palatine nerve of the subject, a        sphenopalatine nerve of the subject, a communicating branch        between a maxillary nerve and an SPG of the subject, a        nasopalatine nerve of the subject, a posterior nasal nerve of        the subject, an infraorbital nerve of the subject, an otic        ganglion of the subject, an afferent fiber going into the otic        ganglion of the subject, an efferent fiber going out of the otic        ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject; and    -   configuring the signal so as to cause an increase in molecular        passage between a central nervous system (CNS) of the subject        and another body compartment of the subject, so as to facilitate        a diagnosis of the AD.

There is further provided, in accordance with an embodiment of thepresent invention, a method for diagnosing Alzheimer's disease (AD),including presenting an odorant to an air passage of the subject, theodorant having been selected for presentation to the air passage becauseit is such as to cause an increase in molecular passage between acentral nervous system (CNS) of the subject and another body compartmentof the subject, so as to facilitate a diagnosis of the AD.

There is still further provided, in accordance with an embodiment of thepresent invention, a method for diagnosing Alzheimer's disease (AD),including:

-   -   applying an electrical signal to at least one site of a subject,        the site selected from the list consisting of: a sphenopalatine        ganglion (SPG) of the subject, an anterior ethmoidal nerve of        the subject, a posterior ethmoidal nerve of the subject, a        communicating branch between an anterior ethmoidal nerve and a        retro-orbital branch of an SPG of the subject, a communicating        branch between a posterior ethmoidal nerve and a retro-orbital        branch of an SPG of the subject, a greater palatine nerve of the        subject, a lesser palatine nerve of the subject, a        sphenopalatine nerve of the subject, a communicating branch        between a maxillary nerve and an SPG of the subject, a        nasopalatine nerve of the subject, a posterior nasal nerve of        the subject, an infraorbital nerve of the subject, an otic        ganglion of the subject, an afferent fiber going into the otic        ganglion of the subject, an efferent fiber going out of the otic        ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject; and    -   configuring the signal so as to cause an increase in molecular        passage between cerebrospinal fluid (CSF) of the subject and        another body fluid of the subject, so as to facilitate a        diagnosis of the AD.

There is yet further provided, in accordance with an embodiment of thepresent invention, a method for diagnosing Alzheimer's disease (AD),including presenting an odorant to an air passage of the subject, theodorant having been selected for presentation to the air passage becauseit is such as to cause an increase in molecular passage betweencerebrospinal fluid (CSF) of the subject and another body fluid of thesubject, so as to facilitate a diagnosis of the AD.

There is also provided, in accordance with an embodiment of the presentinvention, a method for diagnosing Alzheimer's disease (AD), including:

-   -   applying an electrical signal to at least one site of a subject,        the site selected from the list consisting of: a sphenopalatine        ganglion (SPG) of the subject, an anterior ethmoidal nerve of        the subject, a posterior ethmoidal nerve of the subject, a        communicating branch between an anterior ethmoidal nerve and a        retro-orbital branch of an SPG of the subject, a communicating        branch between a posterior ethmoidal nerve and a retro-orbital        branch of an SPG of the subject, a greater palatine nerve of the        subject, a lesser palatine nerve of the subject, a        sphenopalatine nerve of the subject, a communicating branch        between a maxillary nerve and an SPG of the subject, a        nasopalatine nerve of the subject, a posterior nasal nerve of        the subject, an infraorbital nerve of the subject, an otic        ganglion of the subject, an afferent fiber going into the otic        ganglion of the subject, an efferent fiber going out of the otic        ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject; and    -   configuring the signal so as to cause an increase in molecular        passage between cerebrospinal fluid (CSF) of the subject and a        tissue of the subject, so as to facilitate a diagnosis of the        AD.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method for diagnosing Alzheimer's disease (AD),including presenting an odorant to an air passage of the subject, theodorant having been selected for presentation to the air passage becauseit is such as to cause an increase in molecular passage betweencerebrospinal fluid (CSF) of the subject and a tissue of the subject, soas to facilitate a diagnosis of the AD.

In an embodiment, the method includes presenting in association with theodorant an analgesic in a dosage configured to reduce a sensationassociated with the presenting of the odorant. For some applications,the air passage includes a nasal cavity or a throat of the patient, andpresenting the odorant includes presenting the odorant to the nasalcavity or the throat.

For some applications, the odorant is selected from the list consistingof: propionic acid, cyclohexanone, and amyl acetate, and presenting theodorant includes presenting the selected odorant.

Alternatively or additionally, the odorant is selected from the listconsisting of: acetic acid, citric acid, carbon dioxide, sodiumchloride, and ammonia, and presenting the odorant includes presentingthe selected odorant.

Further alternatively or additionally, the odorant is selected from thelist consisting of: menthol, alcohol, nicotine, piperine, gingerol,zingerone, allyl isothiocyanate, cinnamaldehyde, cuminaldehyde,2-propenyl/2-phenylethyl isothiocyanate, thymol, and eucalyptol, andpresenting the odorant includes presenting the selected odorant.

In an embodiment, presenting the odorant includes presenting a capsulefor placement within a mouth of the patient, the capsule beingconfigured to dissolve upon contact with salivary liquids of thepatient, whereupon the odorant is presented to the air passage.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, apparatus for treating Alzheimer's disease (AD),including a stimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of a        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        clearance of an AD-related constituent of a central nervous        system (CNS) of the subject, from a brain of the subject to a        systemic blood circulation of the subject, so as to treat the        AD.

There is still additionally provided, in accordance with an embodimentof the present invention, apparatus for treating Alzheimer's disease(AD), including a stimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of a        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        clearance of an AD-related constituent of a central nervous        system (CNS) of the subject, from a brain of the subject to a        systemic blood circulation of the subject, so as to treat the        AD.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for treating Alzheimer's disease (AD), including astimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of a        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        clearance of an AD-related constituent of a central nervous        system (CNS) of the subject, from cerebrospinal fluid (CSF) of        the subject to a systemic blood circulation of the subject, so        as to treat the AD.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for treating Alzheimer's disease (AD),including a stimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of a        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        clearance of an AD-related constituent of a central nervous        system (CNS) of the subject, from cerebrospinal fluid (CSF) of        the subject to a systemic blood circulation of the subject, so        as to treat the AD.

In an embodiment, the stimulator is adapted to directly stimulate theSPG.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus for treating Alzheimer's disease (AD),including a stimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of the        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in passage        from a systemic blood circulation of the subject into a central        nervous system (CNS) of the subject, of a pharmaceutical agent        supplied to the systemic blood circulation, so as to treat the        AD.

There is yet further provided, in accordance with an embodiment of thepresent invention, apparatus for treating Alzheimer's disease (AD),including a stimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of the        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in passage        from a systemic blood circulation of the subject into a central        nervous system (CNS) of the subject, of a pharmaceutical agent        supplied to the systemic blood circulation, so as to treat the        AD.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for treating Alzheimer's disease (AD), including astimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of the        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and configure the stimulation        so as to cause an increase in cerebral blood flow (CBF) of the        subject, so as to treat the AD.

There is additionally provided, in accordance with an embodiment of thepresent invention, apparatus for treating Alzheimer's disease (AD),including a stimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of the        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in cerebral        blood flow (CBF) of the subject, so as to treat the AD.

There is still additionally provided, in accordance with an embodimentof the present invention, apparatus for diagnosing Alzheimer's disease(AD), including a stimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of a        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        molecular passage between a central nervous system (CNS) of the        subject and another body compartment of the subject, so as to        facilitate a diagnosis of the AD.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, apparatus for diagnosing Alzheimer's disease(AD), including a stimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of a        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        molecular passage between a central nervous system (CNS) of the        subject and another body compartment of the subject, so as to        facilitate a diagnosis of the AD.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for diagnosing Alzheimer's disease (AD), includinga stimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of a        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        molecular passage between cerebrospinal fluid (CSF) of the        subject and another body fluid of the subject, so as to        facilitate a diagnosis of the AD.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for diagnosing Alzheimer's disease (AD),including a stimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of a        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        molecular passage between cerebrospinal fluid (CSF) of the        subject and another body fluid of the subject, so as to        facilitate a diagnosis of the AD.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus for diagnosing Alzheimer's disease (AD),including a stimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of a        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        molecular passage between cerebrospinal fluid (CSF) of the        subject and a tissue of the subject, so as to facilitate a        diagnosis of the AD.

There is yet further provided, in accordance with an embodiment of thepresent invention, apparatus for diagnosing Alzheimer's disease (AD),including a stimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of a        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        molecular passage between cerebrospinal fluid (CSF) of the        subject and a tissue of the subject, so as to facilitate a        diagnosis of the AD.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for treating Alzheimer's disease (AD), including astimulator adapted to:

-   -   apply an electrical signal to at least one site of a subject,        the site selected from the list consisting of: a sphenopalatine        ganglion (SPG) of the subject, an anterior ethmoidal nerve of        the subject, a posterior ethmoidal nerve of the subject, a        communicating branch between an anterior ethmoidal nerve and a        retro-orbital branch of an SPG of the subject, a communicating        branch between a posterior ethmoidal nerve and a retro-orbital        branch of an SPG of the subject, a greater palatine nerve of the        subject, a lesser palatine nerve of the subject, a        sphenopalatine nerve of the subject, a communicating branch        between a maxillary nerve and an SPG of the subject, a        nasopalatine nerve of the subject, a posterior nasal nerve of        the subject, an infraorbital nerve of the subject, an otic        ganglion of the subject, an afferent fiber going into the otic        ganglion of the subject, an efferent fiber going out of the otic        ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject, and    -   configure the signal so as to cause an increase in clearance of        an AD-related constituent of a central nervous system (CNS) of        the subject, from a brain of the subject to a systemic blood        circulation of the subject, so as to treat the AD.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for treating Alzheimer's disease (AD), including astimulator adapted to present an odorant to an air passage of a subject,the odorant having been selected for presentation to the air passagebecause it is such as to cause an increase in clearance of an AD-relatedconstituent of a central nervous system (CNS) of the subject fromcerebrospinal fluid (CSF) of the subject to a systemic blood circulationof the subject, so as to treat the AD.

There is additionally provided, in accordance with an embodiment of thepresent invention, apparatus for treating Alzheimer's disease (AD),including a stimulator adapted to apply an electrical signal to at leastone site of a subject, the site selected from the list consisting of: asphenopalatine ganglion (SPG) of the subject, an anterior ethmoidalnerve of the subject, a posterior ethmoidal nerve of the subject, acommunicating branch between an anterior ethmoidal nerve and aretro-orbital branch of an SPG of the subject, a communicating branchbetween a posterior ethmoidal nerve and a retro-orbital branch of an SPGof the subject, a greater palatine nerve of the subject, a lesserpalatine nerve of the subject, a sphenopalatine nerve of the subject, acommunicating branch between a maxillary nerve and an SPG of thesubject, a nasopalatine nerve of the subject, a posterior nasal nerve ofthe subject, an infraorbital nerve of the subject, an otic ganglion ofthe subject, an afferent fiber going into the otic ganglion of thesubject, an efferent fiber going out of the otic ganglion of thesubject, a vidian nerve of the subject, a greater superficial petrosalnerve of the subject, and a lesser deep petrosal nerve of the subject,and

-   -   configure the signal so as to cause an increase in passage from        a systemic blood circulation of the subject into a central        nervous system (CNS) of the subject, of a pharmaceutical agent        supplied to the systemic blood circulation, so as to treat the        AD.

There is still additionally provided, in accordance with an embodimentof the present invention, apparatus for treating Alzheimer's disease(AD), including a stimulator adapted to present an odorant to an airpassage of the subject, the odorant having been selected forpresentation to the air passage because it is such as to cause anincrease in passage from a systemic blood circulation of the subjectinto a central nervous system (CNS) of the subject, of a pharmaceuticalagent supplied to the systemic blood circulation, so astotreatthe AD.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, apparatus for treating Alzheimer's disease (AD),including a stimulator adapted to:

-   -   apply an electrical signal to at least one site of a subject,        the site selected from the list consisting of: a sphenopalatine        ganglion (SPG) of the subject, an anterior ethmoidal nerve of        the subject, a posterior ethmoidal nerve of the subject, a        communicating branch between an anterior ethmoidal nerve and a        retro-orbital branch of an SPG of the subject, a communicating        branch between a posterior ethmoidal nerve and a retro-orbital        branch of an SPG of the subject, a greater palatine nerve of the        subject, a lesser palatine nerve of the subject, a        sphenopalatine nerve of the subject, a communicating branch        between a maxillary nerve and an SPG of the subject, a        nasopalatine nerve of the subject, a posterior nasal nerve of        the subject, an infraorbital nerve of the subject, an otic        ganglion of the subject, an afferent fiber going into the otic        ganglion of the subject, an efferent fiber going out of the otic        ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject, and    -   configure the signal so as to cause an increase in cerebral        blood flow (CBF) of the subject, so as to treat the AD.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for treating Alzheimer's disease (AD), including astimulator adapted to present an odorant to an air passage of thesubject, the odorant having been selected for presentation to the airpassage because it is such as to cause an increase in cerebral bloodflow (CBF) of the subject, so as to treat the AD.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for diagnosing Alzheimer's disease (AD),including a stimulator adapted to:

-   -   apply an electrical signal to at least one site of a subject,        the site selected from the list consisting of: a sphenopalatine        ganglion (SPG) of the subject, an anterior ethmoidal nerve of        the subject, a posterior ethmoidal nerve of the subject, a        communicating branch between an anterior ethmoidal nerve and a        retro-orbital branch of an SPG of the subject, a communicating        branch between a posterior ethmoidal nerve and a retro-orbital        branch of an SPG of the subject, a greater palatine nerve of the        subject, a lesser palatine nerve of the subject, a        sphenopalatine nerve of the subject, a communicating branch        between a maxillary nerve and an SPG of the subject, a        nasopalatine nerve of the subject, a posterior nasal nerve of        the subject, an infraorbital nerve of the subject, an otic        ganglion of the subject, an afferent fiber going into the otic        ganglion of the subject, an efferent fiber going out of the otic        ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject, and    -   configure the signal so as to cause an increase in molecular        passage between a central nervous system (CNS) of the subject        and another body compartment of the subject, so as to facilitate        a diagnosis of the AD.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus for diagnosing Alzheimer's disease (AD),including a stimulator adapted to present an odorant to an air passageof the subject, the odorant having been selected for presentation to theair passage because it is such as to cause an increase in molecularpassage between a central nervous system (CNS) of the subject andanother body compartment of the subject, so as to facilitate a diagnosisof the AD.

There is yet further provided, in accordance with an embodiment of thepresent invention, apparatus for diagnosing Alzheimer's disease (AD),including a stimulator adapted to:

-   -   apply an electrical signal to at least one site of a subject,        the site selected from the list consisting of: a sphenopalatine        ganglion (SPG) of the subject, an anterior ethmoidal nerve of        the subject, a posterior ethmoidal nerve of the subject, a        communicating branch between an anterior ethmoidal nerve and a        retro-orbital branch of an SPG of the subject, a communicating        branch between a posterior ethmoidal nerve and a retro-orbital        branch of an SPG of the subject, a greater palatine nerve of the        subject, a lesser palatine nerve of the subject, a        sphenopalatine nerve of the subject, a communicating branch        between a maxillary nerve and an SPG of the subject, a        nasopalatine nerve of the subject, a posterior nasal nerve of        the subject, an infraorbital nerve of the subject, an otic        ganglion of the subject, an afferent fiber going into the otic        ganglion of the subject, an efferent fiber going out of the otic        ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject, and    -   configure the signal so as to cause an increase in molecular        passage between cerebrospinal fluid (CSF) of the subject and        another body fluid of the subject, so as to facilitate a        diagnosis of the AD.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for diagnosing Alzheimer's disease (AD), includinga stimulator adapted to present an odorant to an air passage of thesubject, the odorant having been selected for presentation to the airpassage because it is such as to cause an increase in molecular passagebetween cerebrospinal fluid (CSF) of the subject and another body fluidof the subject, so as to facilitate a diagnosis of the AD.

There is additionally provided, in accordance with an embodiment of thepresent invention, apparatus for diagnosing Alzheimer's disease (AD),including a stimulator adapted to:

-   -   apply an electrical signal to at least one site of a subject,        the site selected from the list consisting of: a sphenopalatine        ganglion (SPG) of the subject, an anterior ethmoidal nerve of        the subject, a posterior ethmoidal nerve of the subject, a        communicating branch between an anterior ethmoidal nerve and a        retro-orbital branch of an SPG of the subject, a communicating        branch between a posterior ethmoidal nerve and a retro-orbital        branch of an SPG of the subject, a greater palatine nerve of the        subject, a lesser palatine nerve of the subject, a        sphenopalatine nerve of the subject, a communicating branch        between a maxillary nerve and an SPG of the subject, a        nasopalatine nerve of the subject, a posterior nasal nerve of        the subject, an infraorbital nerve of the subject, an otic        ganglion of the subject, an afferent fiber going into the otic        ganglion of the subject, an efferent fiber going out of the otic        ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject, and    -   configure the signal so as to cause an increase in molecular        passage between cerebrospinal fluid (CSF) of the subject and a        tissue of the subject, so as to facilitate a diagnosis of the        AD.

There is still additionally provided, in accordance with an embodimentof the present invention, apparatus for diagnosing Alzheimer's disease(AD), including a stimulator adapted to present an odorant to an airpassage of the subject, the odorant having been selected forpresentation to the air passage because it is such as to cause anincrease in molecular passage between cerebrospinal fluid (CSF) of thesubject and a tissue of the subject, so as to facilitate a diagnosis ofthe AD.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, apparatus for treating Alzheimer's disease (AD),including:

-   -   an odorant-storage vessel;    -   an odorant for storage within the odorant-storage vessel, the        odorant being capable of increasing clearance of an AD-related        constituent of a central nervous system (CNS) of the subject        from cerebrospinal fluid (CSF) of the subject to a systemic        blood circulation of the subject; and    -   an odorant-delivery element, adapted to present the odorant to        an air passage of the patient, so as to treat the AD.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for treating Alzheimer's disease (AD), including:

-   -   an odorant-storage vessel;    -   an odorant for storage within the odorant-storage vessel, the        odorant being capable of increasing passage, from a systemic        blood circulation of a subject into a central nervous system        (CNS) of the subject, of a pharmaceutical agent supplied to the        systemic blood circulation; and    -   an odorant-delivery element, adapted to present the odorant to        an air passage of the patient, so as to treat the AD.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for treating Alzheimer's disease (AD),including:

-   -   an odorant-storage vessel;    -   an odorant for storage within the odorant-storage vessel, the        odorant being capable of increasing cerebral blood flow (CBF) of        the subject; and    -   an odorant-delivery element, adapted to present the odorant to        an air passage of the patient, so as to treat the AD.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus for diagnosing Alzheimer's disease (AD),including:

-   -   an odorant-storage vessel;    -   an odorant for storage within the odorant-storage vessel, the        odorant being capable of increasing molecular passage between a        central nervous system (CNS) of the subject and another body        compartment of the subject; and    -   an odorant-delivery element, adapted to present the odorant to        an air passage of the patient, so as to facilitate a diagnosis        of the AD.

There is yet further provided, in accordance with an embodiment of thepresent invention, apparatus for diagnosing Alzheimer's disease (AD),including:

-   -   an odorant-storage vessel;    -   an odorant for storage within the odorant-storage vessel, the        odorant being capable of increasing molecular passage between        cerebrospinal fluid (CSF) of the subject and another body fluid        of the subject; and    -   an odorant-delivery element, adapted to present the odorant to        an air passage of the patient, so as to facilitate a diagnosis        of the AD.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for diagnosing Alzheimer's disease (AD), including:

-   -   an odorant-storage vessel;    -   an odorant for storage within the odorant-storage vessel, the        odorant being capable of increasing molecular passage between        cerebrospinal fluid (CSF) of the subject and a tissue of the        subject; and    -   an odorant-delivery element, adapted to present the odorant to        an air passage of the patient, so as to facilitate a diagnosis        of the AD.

In an embodiment, the odorant-storage vessel in combination with theodorant-delivery element includes an aqueous spray nasal inhaler.

In an embodiment, the odorant-storage vessel in combination with theodorant-delivery element includes a metered dose nasal inhaler.

In an embodiment, the odorant-storage vessel in combination with theodorant-delivery element includes an air-dilution olfactometer.

There is also provided, in accordance with an embodiment of the presentinvention, a method for facilitating a diagnosis of a condition of apatient, including:

-   -   stimulating a modulation target site of the patient at a level        sufficient to increase permeability of a blood-brain barrier        (BBB) of the patient; and    -   administering a diagnostic agent capable of passing through the        BBB and into a central nervous system (CNS) of the patient while        the permeability of the BBB is increased.

There is further provided, in accordance with an embodiment of thepresent invention, a method for facilitating a diagnosis of a conditionof a patient, including:

-   -   stimulating a modulation target site of the patient at a level        sufficient to increase permeability of a blood-brain barrier        (BBB) of the patient; and    -   receiving a constituent of a central nervous system (CNS) of the        patient that passes from the CNS and through the BBB while the        permeability of the BBB is increased.

There is still further provided, in accordance with an embodiment of thepresent invention, a method for facilitating a diagnosis of a conditionof a subject, including:

-   -   applying a current to a site of the subject selected from the        list consisting of: a sphenopalatine ganglion (SPG) of the        subject, and a neural tract originating in or leading to the        SPG;    -   configuring the current to increase conductance of molecules        from brain tissue of the subject through a blood brain barrier        (BBB) of the subject into a systemic blood circulation of the        subject; and    -   sensing a quantity of the molecules from a site outside of the        brain of the subject, following initiation of application of the        current.

For some applications, sensing the quantity of the molecules includessampling a fluid of the subject selected from the list consisting of:blood, plasma, serum, ascites fluid, and urine.

For some applications, the method includes determining adiagnostically-relevant parameter responsive to sensing the quantity ofthe molecules.

For some applications, the method includes administering ahyperosmolarity-inducing agent to the subject at a dosage sufficient toaugment an increase in conductance of the molecules caused by theapplication of the current. Alternatively or additionally, the methodincludes inducing a state of dehydration of the subject, of an extentsufficient to augment an increase in conductance of the molecules causedby the application of the current.

For some applications, the method includes administering an agent to thesubject that modulates synthesis or metabolism of nitric-oxide (NO) inblood vessels of the brain, at a dosage sufficient to augment anincrease in conductance of the molecules caused by the application ofthe current.

For some applications, applying the current includes implanting anelectrode at the site, designated to remain in the subject for a periodgreater than about one month. Alternatively, for some applications,applying the current includes implanting an electrode at the site,designated to remain in the subject for a period less than about oneweek.

For some applications, applying the current includes implanting acontrol unit in a nasal cavity of the subject. For some applications,applying the current includes implanting a control unit at a lower sideof a bony palate of the subject. For some applications, applying thecurrent includes implanting one or more electrodes in a nasal cavity ofthe subject. For some applications, implanting includes inserting aflexible electrode through a nostril of the subject.

There is also provided, in accordance with an embodiment of the presentinvention, a method for facilitating a diagnosis of a condition of acentral nervous system (CNS) of a subject, including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of the        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        molecular passage between the CNS and another body compartment        of the subject, so as to facilitate the diagnosis of the CNS        condition.

In an embodiment, the method includes measuring a constituent of theother body compartment.

For some applications, stimulating the SPG-related tissue includesdirectly stimulating the SPG.

For some applications, the other body compartment includes a systemicblood circulation of the subject, and configuring the stimulationincludes configuring the stimulation so as to cause the increase inmolecular passage between the CNS and the systemic blood circulation.Alternatively or additionally, the other body compartment includesplasma of the subject, and configuring the stimulation includesconfiguring the stimulation so as to cause the increase in molecularpassage between the CNS and the plasma. Further alternatively oradditionally, the other body compartment includes serum of the subject,and configuring the stimulation includes configuring the stimulation soas to cause the increase in molecular passage between the CNS and theserum. Still further alternatively or additionally, the other bodycompartment is ascites of the subject, and configuring the stimulationincludes configuring the stimulation so as to cause the increase inmolecular passage between the CNS and the ascites.

For some applications, the CNS condition includes Parkinson's disease,and configuring the stimulation includes configuring the stimulation soas to facilitate the diagnosis of the Parkinson's disease. For someapplications, the CNS condition includes epilepsy, and configuring thestimulation includes configuring the stimulation so as to facilitate thediagnosis of the epilepsy. For some applications, the CNS conditionincludes amyotrophic lateral sclerosis (ALS), and configuring thestimulation includes configuring the stimulation so as to facilitate thediagnosis of the ALS. For some applications, the CNS condition includesmultiple sclerosis (MS), and configuring the stimulation includesconfiguring the stimulation so as to facilitate the diagnosis of the MS.

For some applications, stimulating the SPG-related tissue includesimplanting an electrode at the site, designated to remain in the subjectfor a period greater than about one month. Alternatively, for someapplications, stimulating the SPG-related tissue includes implanting anelectrode at the site, designated to remain in the subject for a periodless than about one week.

For some applications, stimulating the SPG-related tissue includesimplanting a control unit in a nasal cavity of the subject. For someapplications, stimulating the SPG-related tissue includes implanting acontrol unit at a lower side of a bony palate of the subject.

For some applications, the method includes correlating an abnormalconcentration of the constituent to a pathology of the CNS condition.

For some applications, the constituent is selected from the groupconsisting of: a protein, a hormone, an antibody, an electrolyte, aneuropeptide, and an enzyme, and measuring the constituent includesmeasuring the selected constituent.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method for facilitating a diagnosis of a conditionof a central nervous system (CNS) of a subject, including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of the        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        molecular passage between cerebrospinal fluid (CSF) of the        subject and another body fluid of the subject, so as to        facilitate the diagnosis of the CNS condition.

In an embodiment, the method includes measuring a constituent of theother body fluid.

For some applications, stimulating the SPG-related tissue includesdirectly stimulating the SPG.

For some applications, the method includes correlating an abnormalconcentration of the constituent to a pathology of the CNS condition.

For some applications, the constituent is selected from the groupconsisting of: a protein, a hormone, an antibody, an electrolyte, aneuropeptide, and an enzyme, and measuring the constituent includesmeasuring the selected constituent.

For some applications, the other body fluid is selected from the listconsisting of: whole blood, plasma, serum, and ascites, and measuringthe constituent includes sampling the selected fluid.

For some applications, measuring the constituent includes extracting theother body fluid from tissue of the subject.

For some applications, applying the current includes implanting anelectrode at the site, designated to remain in the subject for a periodgreater than about one month. Alternatively, for some applications,applying the current includes implanting an electrode at the site,designated to remain in the subject for a period less than about oneweek.

For some applications, applying the current includes implanting acontrol unit in a nasal cavity of the subject. For some applications,applying the current includes implanting a control unit at a lower sideof a bony palate of the subject.

For some applications, measuring the constituent includes measuring aplurality of constituents. For some applications, the method includesdetermining a diagnostic result according to the interrelation betweenconcentrations of the constituents.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method for facilitating a diagnosis of acondition of a central nervous system (CNS) of a subject, including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of the        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        molecular passage between cerebrospinal fluid (CSF) of the        subject and a tissue of the subject, so as to facilitate a        diagnosis of the CNS condition.

In an embodiment, the method includes measuring a constituent of thetissue.

For some applications, stimulating the SPG-related tissue includesdirectly stimulating the SPG.

For some applications, the method includes correlating an abnormalconcentration of the constituent to a pathology of the CNS condition.

For some applications, the constituent is selected from the groupconsisting of: a protein, a hormone, an antibody, an electrolyte, aneuropeptide, and an enzyme, and measuring the constituent includesmeasuring the selected constituent.

For some applications, measuring the constituent includes measuring aplurality of constituents of the tissue. For some applications, themethod includes determining a diagnostic result according to theinterrelation between concentrations of the constituents of the tissue.

There is still additionally provided, in accordance with an embodimentof the present invention, a method for facilitating a diagnosis of acondition of a central nervous system (CNS) of a subject, including:

-   -   applying an electrical signal to at least one site of the        subject, the site selected from the list consisting of: a        sphenopalatine ganglion (SPG) of the subject, an anterior        ethmoidal nerve of the subject, a posterior ethmoidal nerve of        the subject, a communicating branch between an anterior        ethmoidal nerve and a retro-orbital branch of an SPG of the        subject, a communicating branch between a posterior ethmoidal        nerve and a retro-orbital branch of an SPG of the subject, a        greater palatine nerve of the subject, a lesser palatine nerve        of the subject, a sphenopalatine nerve of the subject, a        communicating branch between a maxillary nerve and an SPG of the        subject, a nasopalatine nerve of the subject, a posterior nasal        nerve of the subject, an infraorbital nerve of the subject, an        otic ganglion of the subject, an afferent fiber going into the        otic ganglion of the subject, an efferent fiber going out of the        otic ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject; and    -   configuring the signal so as to cause an increase in molecular        passage between the CNS and another body compartment of the        subject, so as to facilitate a diagnosis of the CNS condition.

In an embodiment, the method includes measuring a constituent of theother body compartment.

There is further provided, in accordance with an embodiment of thepresent invention, a method for facilitating a diagnosis of a conditionof a central nervous system (CNS) of a subject, including:

-   -   applying an electrical signal to at least one site of the        subject, the site selected from the list consisting of: a        sphenopalatine ganglion (SPG) of the subject, an anterior        ethmoidal nerve of the subject, a posterior ethmoidal nerve of        the subject, a communicating branch between an anterior        ethmoidal nerve and a retro-orbital branch of an SPG of the        subject, a communicating branch between a posterior ethmoidal        nerve and a retro-orbital branch of an SPG of the subject, a        greater palatine nerve of the subject, a lesser palatine nerve        of the subject, a sphenopalatine nerve of the subject, a        communicating branch between a maxillary nerve and an SPG of the        subject, a nasopalatine nerve of the subject, a posterior nasal        nerve of the subject, an infraorbital nerve of the subject, an        otic ganglion of the subject, an afferent fiber going into the        otic ganglion of the subject, an efferent fiber going out of the        otic ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject; and    -   configuring the signal so as to cause an increase in molecular        passage between cerebrospinal fluid (CSF) of the subject and        another body fluid of the subject, so as to facilitate a        diagnosis of the CNS condition.

In an embodiment, the method includes measuring a constituent of theother body fluid.

There is yet further provided, in accordance with an embodiment of thepresent invention, a method for facilitating a diagnosis of a conditionof a central nervous system (CNS) of a subject, including:

-   -   applying an electrical signal to at least one site of the        subject, the site selected from the list consisting of: a        sphenopalatine ganglion (SPG) of the subject, an anterior        ethmoidal nerve of the subject, a posterior ethmoidal nerve of        the subject, a communicating branch between an anterior        ethmoidal nerve and a retro-orbital branch of an SPG of the        subject, a communicating branch between a posterior ethmoidal        nerve and a retro-orbital branch of an SPG of the subject, a        greater palatine nerve of the subject, a lesser palatine nerve        of the subject, a sphenopalatine nerve of the subject, a        communicating branch between a maxillary nerve and an SPG of the        subject, a nasopalatine nerve of the subject, a posterior nasal        nerve of the subject, an infraorbital nerve of the subject, an        otic ganglion of the subject, an afferent fiber going into the        otic ganglion of the subject, an efferent fiber going out of the        otic ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject; and    -   configuring the signal so as to cause an increase in molecular        passage between cerebrospinal fluid (CSF) of the subject and a        tissue of the subject, so as to facilitate a diagnosis of the        CNS condition.

In an embodiment, the method includes measuring a constituent of thetissue.

There is still further provided, in accordance with an embodiment of thepresent invention, a method for facilitating a diagnosis of a conditionof a central nervous system (CNS) of a subject, the method including:

-   -   stimulating at least one site of the subject by applying an        electrical current to the site, the site selected from the list        consisting of: a sphenopalatine ganglion (SPG) of the subject,        an anterior ethmoidal nerve of the subject, a posterior        ethmoidal nerve of the subject, a communicating branch between        the anterior ethmoidal nerve and the SPG, a communicating branch        between the posterior ethmoidal nerve and the SPG, a nerve of        the pterygoid canal of the subject, a greater palatine nerve of        the subject, a lesser palatine nerve of the subject, a        sphenopalatine nerve of the subject, a communicating branch        between a maxillary nerve of the subject and the SPG, a        nasopalatine nerve of the subject, a posterior nasal nerve of        the subject, an infraorbital nerve of the subject, an otic        ganglion of the subject, an afferent fiber going into the otic        ganglion, and an efferent fiber going out of the otic ganglion;    -   configuring the stimulation so as to cause an increase in        molecular passage between the CNS and another body compartment        of the subject;    -   taking a sample from the body compartment; and    -   determining a level of a constituent of the sample, so as to        facilitate the diagnosis of the CNS condition.

For some applications, the CNS condition includes a neurodegenerativecondition, and determining the level of the constituent includesdetermining the level of the constituent so as to facilitate thediagnosis of the neurodegenerative condition. For some applications, theCNS condition includes a neoplastic process, and determining the levelof the constituent includes determining the level of the constituent soas to facilitate the diagnosis of the neoplastic process. For someapplications, the CNS condition is selected from the list consisting of:an immune-related disorder and an autoimmune-related disorder, anddetermining the level of the constituent includes determining the levelof the constituent so as to facilitate the diagnosis of the selectedcondition. For some applications, the CNS condition includes a CNSinflammatory process, and determining the level of the constituentincludes determining the level of the constituent so as to facilitatethe diagnosis of the CNS inflammatory process.

In an embodiment, the method includes interpreting a low value of thelevel as indicative of an increased likelihood that the subject suffersfrom the CNS condition. For some applications, the method includesinterpreting a high value of the level as indicative of a decreasedlikelihood that the subject suffers from the CNS condition. For someapplications, the body compartment includes a systemic blood circulationof the subject, and configuring the stimulation includes configuring thestimulation so as to cause the increase in molecular passage between theCNS and the systemic blood circulation. Alternatively or additionally,the body compartment includes plasma of the subject, and configuring thestimulation includes configuring the stimulation so as to cause theincrease in molecular passage between the CNS and the plasma. Furtheralternatively or additionally, the body compartment includes serum ofthe subject, and configuring the stimulation includes configuring thestimulation so as to cause the increase in molecular passage between theCNS and the serum. Still further alternatively or additionally, the bodycompartment is ascites of the subject, and configuring the stimulationincludes configuring the stimulation so as to cause the increase inmolecular passage between the CNS and the ascites. For someapplications, the site includes the SPG, and stimulating the siteincludes stimulating the SPG.

For some applications, the CNS condition includes Alzheimer's disease,and interpreting the low value includes interpreting the low value asindicative of the increased likelihood that the subject suffers fromAlzheimer's disease. For some applications, the constituent includesamyloid-beta peptide, and determining the level of the constituentincludes determining the level of the amyloid-beta peptide.Alternatively or additionally, the constituent includes presenilin-1,and determining the level of the constituent includes determining thelevel of the presenilin-1.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method for facilitating a diagnosis of a conditionof a central nervous system (CNS) of a subject, the method including:

-   -   stimulating at least one site of the subject selected from the        list consisting of: a sphenopalatine ganglion (SPG) of the        subject, an anterior ethmoidal nerve of the subject, a posterior        ethmoidal nerve of the subject, a communicating branch between        the anterior ethmoidal nerve and the SPG, a communicating branch        between the posterior ethmoidal nerve and the SPG, a nerve of        the pterygoid canal of the subject, a greater palatine nerve of        the subject, a lesser palatine nerve of the subject, a        sphenopalatine nerve of the subject, a communicating branch        between a maxillary nerve of the subject and the SPG, a        nasopalatine nerve of the subject, a posterior nasal nerve of        the subject, an infraorbital nerve of the subject, an otic        ganglion of the subject, an afferent fiber going into the otic        ganglion, and an efferent fiber going out of the otic ganglion;    -   configuring the stimulation so as to cause an increase in        molecular passage between the CNS and another body compartment        of the subject;    -   taking a sample from the body compartment; and    -   determining a level of a constituent of the sample, so as to        facilitate the diagnosis of the CNS condition.

For some applications, the CNS condition includes a neurodegenerativecondition, and determining the level of the constituent includesdetermining the level of the constituent so as to facilitate thediagnosis of the neurodegenerative condition. For some applications, theCNS condition includes a neoplastic process, and determining the levelof the constituent includes determining the level of the constituent soas to facilitate the diagnosis of the neoplastic process. For someapplications, the CNS condition is selected from the list consisting of:an immune-related disorder and an autoimmune-related disorder, anddetermining the level of the constituent includes determining the levelof the constituent so as to facilitate the diagnosis of the selectedcondition. For some applications, the CNS condition includes a CNSinflammatory process, and determining the level of the constituentincludes determining the level of the constituent so as to facilitatethe diagnosis of the CNS inflammatory process.

In an embodiment, the method includes interpreting a low value of thelevel as indicative of an increased likelihood that the subject suffersfrom the CNS condition. For some applications, the method includesinterpreting a high value of the level as indicative of a decreasedlikelihood that the subject suffers from the CNS condition.

In an embodiment, stimulating includes applying magnetic stimulation tothe site. In an embodiment, stimulating includes applyingelectromagnetic stimulation to the site. In an embodiment, stimulatingincludes applying chemical stimulation to the site. In an embodiment,stimulating includes applying mechanical stimulation to the site.

For some applications, the body compartment includes a systemic bloodcirculation of the subject, and configuring the stimulation includesconfiguring the stimulation so as to cause the increase in molecularpassage between the CNS and the systemic blood circulation.

Alternatively or additionally, the body compartment includes plasma ofthe subject, and configuring the stimulation includes configuring thestimulation so as to cause the increase in molecular passage between theCNS and the plasma. Further alternatively or additionally, the bodycompartment includes serum of the subject, and configuring thestimulation includes configuring the stimulation so as to cause theincrease in molecular passage between the CNS and the serum. Stillfurther alternatively or additionally, the body compartment is ascitesof the subject, and configuring the stimulation includes configuring thestimulation so as to cause the increase in molecular passage between theCNS and the ascites.

For some applications, the site includes the SPG, and stimulating thesite includes stimulating the SPG.

For some applications, the CNS condition includes Alzheimer's disease,and interpreting the low value includes interpreting the low value asindicative of the increased likelihood that the subject suffers fromAlzheimer's disease. For some applications, the constituent includesamyloid-beta peptide, and determining the level of the constituentincludes determining the level of the amyloid-beta peptide.Alternatively or additionally, the constituent includes presenilin-1,and determining the level of the constituent includes determining thelevel of the presenilin-1.

There is also provided, in accordance with an embodiment of the presentinvention, a method for treating a condition of a central nervous system(CNS) of a subject, including:

-   -   applying a current to a site of the subject selected from the        list consisting of: a sphenopalatine ganglion (SPG) of the        subject, and a neural tract originating in or leading to the        SPG;    -   configuring the current to increase clearance of molecules from        brain tissue of the subject through a blood brain barrier (BBB)        of the subject into a systemic blood circulation of the subject,        so as to treat the CNS condition.

For some applications, the molecules include a toxin, and configuringthe current includes configuring the current to increase the clearanceof the toxin from the brain tissue, so as to treat the CNS condition.

For some applications, applying the current includes implanting anelectrode at the site, designated to remain in the subject for a periodgreater than about one month. Alternatively, for some applications,applying the current includes implanting an electrode at the site,designated to remain in the subject for a period less than about oneweek.

For some applications, applying the current includes implanting acontrol unit in a nasal cavity of the subject. For some applications,applying the current includes implanting a control unit at a lower sideof a bony palate of the subject.

There is further provided, in accordance with an embodiment of thepresent invention, a method for treating a condition of a centralnervous system (CNS) of a subject, including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of the        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        clearance of a neurotoxic compound from a brain of the subject        through a blood brain barrier (BBB) of the subject to a systemic        blood circulation of the subject, so as to treat the CNS        condition.

For some applications, stimulating the SPG-related tissue includesdirectly stimulating the SPG.

There is still further provided, in accordance with an embodiment of thepresent invention, a method for treating a condition of a centralnervous system (CNS) of a subject, including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of the        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        clearance of a neurotoxic compound from a brain of the subject        through a blood brain barrier (BBB) of the subject to a systemic        blood circulation of the subject, so as to treat the CNS        condition.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method for treating a condition of a centralnervous system (CNS) of a subject, including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of the        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        clearance of a neurotoxic compound from cerebrospinal fluid        (CSF) of the subject through a blood brain barrier (BBB) of the        subject to a systemic blood circulation of the subject, so as to        treat the CNS condition.

For some applications, stimulating the SPG-related tissue includesdirectly stimulating the SPG.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method for treating a condition of a centralnervous system (CNS) of a subject, including:

-   -   stimulating sphenopalatine ganglion (SPG)-related tissue of the        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG; and    -   configuring the stimulation so as to cause an increase in        clearance of a neurotoxic compound from cerebrospinal fluid        (CSF) of the subject through a blood brain barrier (BBB) of the        subject to a systemic blood circulation of the subject, so as to        treat the CNS condition.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for facilitating a diagnosis of a conditionof a subject, including a stimulator adapted to:

-   -   apply a current to a site of the subject selected from the list        consisting of: a sphenopalatine ganglion (SPG) of the subject,        and a neural tract originating in or leading to the SPG, and    -   configure the current to increase conductance of molecules from        brain tissue of the subject through a blood brain barrier (BBB)        of the subject into a systemic blood circulation of the subject,        so as to facilitate the diagnosis of the condition.

For some applications, the stimulator is adapted to directly stimulatethe SPG.

In an embodiment, the apparatus is adapted to measure a constituent ofthe other body compartment.

There is still additionally provided, in accordance with an embodimentof the present invention, apparatus for facilitating a diagnosis of acondition of a central nervous system (CNS) of a subject, including astimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of the        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        molecular passage between the CNS and another body compartment        of the subject, so as to facilitate the diagnosis of the CNS        condition.

In an embodiment, the apparatus is adapted to measure a constituent ofthe other body compartment.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for facilitating a diagnosis of a conditionof a central nervous system (CNS) of a subject, including a stimulatoradapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of the        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        molecular passage between cerebrospinal fluid (CSF) of the        subject and another body fluid of the subject, so as to        facilitate the diagnosis of the CNS condition.

In an embodiment, the apparatus is adapted to measure a constituent ofthe other body fluid.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for facilitating a diagnosis of a condition of acentral nervous system (CNS) of a subject, including a stimulatoradapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of the        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        molecular passage between cerebrospinal fluid (CSF) of the        subject and a tissue of the subject, so as to facilitate the        diagnosis of the CNS condition.

In an embodiment, the apparatus is adapted to measure a constituent ofthe tissue.

There is additionally provided, in accordance with an embodiment of thepresent invention, apparatus for facilitating a diagnosis of a conditionof a central nervous system (CNS) of a subject, including a stimulatoradapted to:

-   -   apply an electrical signal to at least one site of the subject,        the site selected from the list consisting of: a sphenopalatine        ganglion (SPG) of the subject, an anterior ethmoidal nerve of        the subject, a posterior ethmoidal nerve of the subject, a        communicating branch between an anterior ethmoidal nerve and a        retro-orbital branch of an SPG of the subject, a communicating        branch between a posterior ethmoidal nerve and a retro-orbital        branch of an SPG of the subject, a greater palatine nerve of the        subject, a lesser palatine nerve of the subject, a        sphenopalatine nerve of the subject, a communicating branch        between a maxillary nerve and an SPG of the subject, a        nasopalatine nerve of the subject, a posterior nasal nerve of        the subject, an infraorbital nerve of the subject, an otic        ganglion of the subject, an afferent fiber going into the otic        ganglion of the subject, an efferent fiber going out of the otic        ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject, and    -   configure the signal so as to cause an increase in molecular        passage between the CNS and another body compartment of the        subject, so as to facilitate the diagnosis of the CNS condition.

In an embodiment, the apparatus is adapted to measure a constituent ofthe other body compartment.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, apparatus for facilitating a diagnosis of acondition of a central nervous system (CNS) of a subject, including astimulator adapted to:

-   -   apply an electrical signal to at least one site of the subject,        the site selected from the list consisting of: a sphenopalatine        ganglion (SPG) of the subject, an anterior ethmoidal nerve of        the subject, a posterior ethmoidal nerve of the subject, a        communicating branch between an anterior ethmoidal nerve and a        retro-orbital branch of an SPG of the subject, a communicating        branch between a posterior ethmoidal nerve and a retro-orbital        branch of an SPG of the subject, a greater palatine nerve of the        subject, a lesser palatine nerve of the subject, a        sphenopalatine nerve of the subject, a communicating branch        between a maxillary nerve and an SPG of the subject, a        nasopalatine nerve of the subject, a posterior nasal nerve of        the subject, an infraorbital nerve of the subject, an otic        ganglion of the subject, an afferent fiber going into the otic        ganglion of the subject, an efferent fiber going out of the otic        ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject, and    -   configure the signal so as to cause an increase in molecular        passage between cerebrospinal fluid (CSF) of the subject and        another body fluid of the subject, so as to facilitate the        diagnosis of the CNS condition.

In an embodiment, the apparatus is adapted to measure a constituent ofthe other body fluid.

There is still additionally provided, in accordance with an embodimentof the present invention, apparatus for facilitating a diagnosis of acondition of a central nervous system (CNS) of a subject, including astimulator adapted to:

-   -   apply an electrical signal to at least one site of the subject,        the site selected from the list consisting of: a sphenopalatine        ganglion (SPG) of the subject, an anterior ethmoidal nerve of        the subject, a posterior ethmoidal nerve of the subject, a        communicating branch between an anterior ethmoidal nerve and a        retro-orbital branch of an SPG of the subject, a communicating        branch between a posterior ethmoidal nerve and a retro-orbital        branch of an SPG of the subject, a greater palatine nerve of the        subject, a lesser palatine nerve of the subject, a        sphenopalatine nerve of the subject, a communicating branch        between a maxillary nerve and an SPG of the subject, a        nasopalatine nerve of the subject, a posterior nasal nerve of        the subject, an infraorbital nerve of the subject, an otic        ganglion of the subject, an afferent fiber going into the otic        ganglion of the subject, an efferent fiber going out of the otic        ganglion of the subject, a vidian nerve of the subject, a        greater superficial petrosal nerve of the subject, and a lesser        deep petrosal nerve of the subject, and    -   configure the signal so as to cause an increase in molecular        passage between cerebrospinal fluid (CSF) of the subject and a        tissue of the subject, so as to facilitate the diagnosis of the        CNS condition.

In an embodiment, the apparatus is adapted to measure a constituent ofthe tissue.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for treating a condition of a central nervoussystem (CNS) of a subject, including a stimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of the        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        clearance of a neurotoxic compound from a brain of the subject        through a blood brain barrier (BBB) of the subject to a systemic        blood circulation of the subject, so as to treat the CNS        condition.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for treating a condition of a centralnervous system (CNS) of a subject, including a stimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of the        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        clearance of a neurotoxic compound from a brain of the subject        through a blood brain barrier (BBB) of the subject to a systemic        blood circulation of the subject, so as to treat the CNS        condition.

There is yet further provided, in accordance with an embodiment of thepresent invention, apparatus for treating a condition of a centralnervous system (CNS) of a subject, including a stimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of the        subject by applying an electrical signal to the SPG-related        tissue, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        clearance of a neurotoxic compound from cerebrospinal fluid        (CSF) of the subject through a blood brain barrier (BBB) of the        subject to a systemic blood circulation of the subject, so as to        treat the CNS condition.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus for treating a condition of a centralnervous system (CNS) of a subject, including a stimulator adapted to:

-   -   stimulate sphenopalatine ganglion (SPG)-related tissue of the        subject by presenting an odorant to an air passage of the        subject, the SPG-related tissue selected from: an SPG of the        subject and nerve fibers of the subject which are directly        anatomically connected to the SPG, and    -   configure the stimulation so as to cause an increase in        clearance of a neurotoxic compound from cerebrospinal fluid        (CSF) of the subject through a blood brain barrier (BBB) of the        subject to a systemic blood circulation of the subject, so as to        treat the CNS condition.

The present invention will be more fully understood from the followingdetailed description of the preferred embodiments thereof, takentogether with the drawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B are schematic pictorial views of a fully implantablestimulator for stimulation of the SPG, in accordance with preferredembodiments of the present invention;

FIG. 2 is a schematic pictorial view of another stimulator forstimulation of the SPG, in accordance with a preferred embodiment of thepresent invention;

FIG. 3 is a schematic block diagram illustrating circuitry for use withthe stimulator shown in FIGS. 1A and 1B, in accordance with a preferredembodiment of the present invention;

FIG. 4 is a schematic block diagram illustrating circuitry for use withthe stimulator shown in FIG. 2, in accordance with a preferredembodiment of the present invention;

FIGS. 5A and 5B are schematic illustrations depicting different modes ofoperation of stimulators such as those shown in FIGS. 1A, 1B, and 2, inaccordance with preferred embodiments of the present invention;

FIG. 6 is a schematic illustration of a mode of operation of thestimulators shown in FIGS. 1A, 1B, and 2, synchronized with a drugdelivery system, in accordance with a preferred embodiment of thepresent invention;

FIG. 7 is a schematic block diagram illustrating circuitry for use withthe stimulator shown in FIGS. 1A and 1B, where the stimulator is drivenby an external controller and energy source using a modulator and ademodulator, in accordance with a preferred embodiment of the presentinvention;

FIG. 8 depicts sample modulator and demodulator functions for use withthe circuitry of FIG. 7, in accordance with a preferred embodiment ofthe present invention;

FIGS. 9, 10A, and 10B are schematic diagrams illustrating furthercircuitry for use with implantable stimulators, in accordance withrespective preferred embodiments of the present invention;

FIGS. 11 and 12 are bar graphs showing experimental data collected inaccordance with a preferred embodiment of the present invention;

FIG. 13 is a schematic illustration of a sensor for application to ablood vessel, in accordance with a preferred embodiment of the presentinvention;

FIG. 14 is a schematic sectional illustration of a nasal inhaler, foruse in presenting an odorant to a subject, in accordance with apreferred embodiment of the present invention;

FIGS. 15-17 are graphs showing the results from SPG stimulationexperiments carried out in accordance with embodiments of the presentinvention; and

FIG. 18 is a schematic illustration of an implantable stimulator forstimulation of an MTS, in accordance with an embodiment of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

FIGS. 1A and 1B are schematic pictorial views of a fully-implantablestimulator 4, for stimulation of the sphenopalatine ganglion (SPG) 6, a“modulation target site” (MTS), or other parasympathetic site of apatient, in accordance with preferred embodiments of the presentinvention. In FIGS. 1A and 1B, a human nasal cavity 2 is shown. In FIG.1A, stimulator 4 is implanted adjacent to SPG 6. In FIG. 1B, stimulator4 is implanted between the hard palate and the mucoperiosteum (notshown) of the roof of the mouth. Branches of parasympathetic neuronscoming from SPG 6 extend to the middle cerebral and anterior cerebralarteries (not shown). Preferably, one or more relatively shortelectrodes 7 extend from stimulator 4 to contact or to be in a vicinityof SPG 6 or of nerves innervating SPG 6 (e.g., postganglionicparasympathetic trunks thereof).

In the present patent application, a “modulation target site” consistsof:

-   -   a sphenopalatine ganglion (SPG) (also called a pterygopalatine        ganglion);    -   an anterior ethmoidal nerve;    -   a posterior ethmoidal nerve;    -   a communicating branch between the anterior ethmoidal nerve and        the SPG (retro-orbital branch);    -   a communicating branch between the posterior ethmoidal nerve and        the SPG (retro-orbital branch);    -   a nerve of the pterygoid canal (also called a vidian nerve),        such as a greater superficial petrosal nerve (a preganglionic        parasympathetic nerve) or a lesser deep petrosal nerve (a        postganglionic sympathetic nerve);    -   a greater palatine nerve;    -   a lesser palatine nerve;    -   a sphenopalatine nerve;    -   a communicating branch between the maxillary nerve and the        sphenopalatine ganglion;    -   a nasopalatine nerve;    -   a posterior nasal nerve;    -   an infraorbital nerve;    -   an otic ganglion;    -   an afferent fiber going into the otic ganglion; and/or    -   an efferent fiber going out of the otic ganglion.

For some applications, stimulator 4 is implanted on top of the bonypalate, in the bottom of the nasal cavity. Alternatively oradditionally, the stimulator is implanted at the lower side of the bonypalate, at the top of the oral cavity. In this instance, one or moreflexible electrodes 7 originating in the stimulator are passed throughthe palatine bone or posterior to the soft palate, so as to be in aposition to stimulate the SPG or its parasympathetic tracts, or anotherMTS. Further alternatively or additionally, the stimulator may bedirectly attached to the SPG and/or to its postganglionicparasympathetic trunk(s) and/or to another MTS.

For some applications, stimulator 4 is delivered to a desired pointwithin nasal cavity 2 by removably attaching stimulator 4 to the distalend of a rigid or slightly flexible introducer rod (not shown) andinserting the rod into one of the patient's nasal passages until thestimulator is properly positioned. As appropriate, the placement processmay be facilitated by fluoroscopy, x-ray guidance, fine endoscopicsurgery (FES) techniques or by any other effective guidance method knownin the art, or by combinations of the aforementioned. Preferably, theambient temperature and/or cerebral blood flow is measured concurrentlywith insertion. The cerebral blood flow may be measured with, forexample, a laser Doppler unit positioned at the patient's forehead ortranscranial Doppler measurements. Verification of proper implantationof the electrodes onto the appropriate neural structure may be performedby activating the device, and generally simultaneously monitoringcerebral blood flow.

The placement process may be performed using techniques described inU.S. Provisional Patent Application 60/426,180 filed Nov. 14, 2002,entitled, “Surgical tools and techniques for stimulation,” or in PCTPublication WO 04/043218 to Gross et al., which are assigned to theassignee of the present patent application and is incorporated herein byreference.

The passage of certain molecules from cerebral blood vessels into thebrain is hindered by the BBB. The endothelium of the capillaries, theplasma membrane of the blood vessels, and the foot processes of theastrocytes all impede uptake by the brain of the molecules. The BBBgenerally allows only small molecules (e.g., hydrophilic molecules ofmolecular weight less than about 200 Da, and lipophilic molecules ofless than about 500 Da) to pass from the circulation into the brain.

In accordance with a preferred embodiment of the present invention,parasympathetic activation induced by current from stimulator 4overcomes the resistance to trans-BBB molecular movement generated bythe endothelium of the cerebral capillaries and the plasma membrane. Forsome applications, therefore, stimulator 4 may be used to transientlyremove a substantial obstacle to the passage of drugs from the blood tothe brain, of diagnostic agents from the systemic blood circulation tothe CNS, and/or of biochemical agents from the CNS to the systemic bloodcirculation. For example, the stimulator may cyclically apply currentfor about two minutes, and subsequently have a rest period of betweenabout 1 and 20 minutes.

It is hypothesized that two neurotransmitters play an important role inthis change in properties of the BBB—vasoactive intestinal polypeptide(VIP) and nitric oxide (NO). (Acetylcholine may also be involved.) VIPis a short peptide, and NO is a gaseous molecule. VIP is believed to bea major factor in facilitating plasma protein extravasation (PPE), whileNO is responsible for vasodilation. For some applications, stimulator 4is adapted to vary parameters of the current applied to the SPG, asappropriate, in order to selectively influence the activity of one orboth of these neurotransmitters. For example, stimulation of theparasympathetic nerve at different frequencies can induce differentialsecretion—low frequencies cause secretion of NO, while high frequencies(e.g., above about 10 Hz) cause secretion of peptides (VIP).

For other applications, a constant level DC signal, or a slowly varyingvoltage ramp is applied, in order to block parasympathetic neuralactivity in affected tissue. Alternatively, similar results can beobtained by stimulating at a rate higher than about 10 Hz, because thistends to exhaust neurotransmitters. Thus, stimulator 4 may be configuredto induce parasympathetic electrical block, in order to causevasoconstriction by mimicking the overall effect of chemical block onthe SPG. This vasoconstrictive effect may be used, for example, tocontrollably prevent or reverse the formation of migraine headaches.This technique of electrical treatment of migraines stands in contrastto methods of the prior art, in which pharmacological agents such aslidocaine are applied so as to induce SPG block.

FIG. 2 is a schematic illustration of a stimulator control unit 8positioned external to a patient's body, in accordance with a preferredembodiment of the present invention. At least one flexible electrode 10preferably extends from control unit 8, through a nostril 12 of thepatient, and to a position within the nasal cavity 14 that is adjacentto SPG 6.

It is to be understood that electrodes 7 (FIGS. 1A and 1B) and 10 mayeach comprise one or more electrodes, e.g., two electrodes, or an arrayof microelectrodes. For applications in which stimulator 4 comprises ametal housing that can function as an electrode, then typically oneelectrode 7 is used, operating in a monopolar mode. Regardless of thetotal number of electrodes in use, typically only a single or a doubleelectrode extends to SPG 6. Other electrodes 7 or 10 or a metal housingof stimulator 4 are preferably temporarily or permanently implanted incontact with other parts of nasal cavity 2.

Each of electrodes 7 and/or 10 preferably comprises a suitableconductive material, for example, a physiologically-acceptable materialsuch as silver, iridium, platinum, a platinum iridium alloy, titanium,nitinol, or a nickel-chrome alloy. For some applications, one or more ofthe electrodes have lengths ranging from about 1 to 5 mm, and diametersranging from about 50 to 100 microns. Each electrode is preferablyinsulated with a physiologically-acceptable material such aspolyethylene, polyurethane, or a co-polymer of either of these. Theelectrodes are preferably spiral in shape, for better contact, and mayhave a hook shaped distal end for hooking into or near the SPG.Alternatively or additionally, the electrodes may comprise simple wireelectrodes, spring-loaded “crocodile” electrodes, or adhesive probes, asappropriate.

In a preferred embodiment of the invention, each one of electrodes 7and/or 10 comprises a substantially smooth surface, except that thedistal end of each such electrode is configured or treated to have alarge surface area. For example, the distal tip may be porousplatinized. Alternatively or additionally, at least the tip of electrode7 or 10, and/or a metal housing of stimulator 4 includes a coatingcomprising an anti-inflammatory drug, such as beclomethasone sodiumphosphate or beclomethasone phosphate. Alternatively, such ananti-inflammatory drug is injected or otherwise applied.

Typically, a determination regarding whether to use a configuration suchas that shown in FIG. 1B or that shown in FIG. 2 is made responsive to afrequency or total number of diagnostic procedures anticipated. Whenthis frequency or total number is high, the preference is for aconfiguration such as that shown in FIG. 1B, while one-time orinfrequent diagnostic procedures indicates for a configuration such asthat shown in FIG. 2.

FIG. 3 is a schematic block diagram illustrating circuitry comprising animplanted unit 20 and an external unit 30, for use with stimulator 4, inaccordance with a preferred embodiment of the present invention.Implanted unit 20 preferably comprises a feedback block 22 and one ormore sensing or signal application electrodes 24. Implanted unit 20typically also comprises an electromagnetic coupler 26, which receivespower and/or sends or receives data signals to or from anelectromagnetic coupler 28 in external unit 30.

External unit 30 preferably comprises a microprocessor 32 which receivesan external control signal 34 (e.g., from a physician or from thepatient), and a feedback signal 36 from feedback block 22. Controlsignal 34 may include, for example, operational parameters such as aschedule of operation, patient parameters such as the patient's weight,or signal parameters, such as desired frequencies or amplitudes of asignal to be applied to the SPG or another MTS. If appropriate, controlsignal 34 can comprise an emergency override signal, entered by thepatient or a healthcare provider to terminate stimulation or to modifyit in accordance with a predetermined program. Microprocessor 32, inturn, preferably processes control signal 34 and feedback signal 36 soas to determine one or more parameters of the electric current to beapplied through electrodes 24. Responsive to this determination,microprocessor 32 typically generates an electromagnetic control signal42 that is conveyed by electromagnetic coupler 28 to electromagneticcoupler 26. Control signal 42 preferably corresponds to a desiredcurrent or voltage to be applied by electrodes 24 to SPG 6 or anotherMTS, and, in a preferred embodiment, inductively drives the electrodes.The configuration of couplers 26 and 28 and/or other circuitry in units20 or 30 may determine the intensity, frequency, shape, monophasic orbiphasic mode, or DC offset of the signal (e.g., a series of pulses)applied to designated tissue.

Power for microprocessor 32 is typically supplied by a battery 44 or,optionally, another DC power supply. Grounding is provided by battery 44or a separate ground 46. If appropriate, microprocessor 32 generates adisplay signal 38 that drives a display block 40 of external unit 30.Typically, but not necessarily, the display is activated to showfeedback data generated by feedback block 22, or to provide a userinterface for the external unit.

Implanted unit 20 is preferably packaged in a case made of titanium,platinum or an epoxy or other suitable biocompatible material. Shouldthe case be made of metal, then the case may serve as a ground electrodeand, therefore, stimulation typically is performed in a monopolar mode.Alternatively, should the case be made of biocompatible plasticmaterial, two electrodes 24 are typically driven to apply current to theSPG or another MTS.

For some applications, the waveform applied by one or more of electrodes24 to designated tissue, such as designated tissue of an MTS (e.g., theSPG) comprises a waveform with an exponential decay, a ramp up or down,a square wave, a sinusoid, a saw tooth, a DC component, or any othershape known in the art to be suitable for application to tissue.Alternatively or additionally, the waveform comprises one or more burstsof short shaped or square pulses—each pulse preferably less than about 1ms in duration. Generally, appropriate waveforms and parameters thereofare determined during an initial test period of external unit 30 andimplanted unit 20. For some applications, the waveform is dynamicallyupdated according to measured physiological parameters, measured duringa period in which unit 20 is stimulating the SPG or another MTS, and/orduring a non-activation (i.e., standby) period.

In the case of migraine treatment, the waveform may take the form of aslowly varying shape, such as a slow saw tooth, or a constant DC level,intended to block outgoing parasympathetic messaging.

FIG. 4 is a schematic block diagram of circuitry for use, for example,in conjunction with control unit 8 (FIG. 2), in accordance with apreferred embodiment of the present invention. An external unit 50comprises a microprocessor 52 supplied by a battery 54 or another DCpower source. Grounding may be provided by battery 54 or by a separateground 56. Microprocessor 52 preferably receives control and feedbacksignals 58 and 68 (analogous to signal 34 and 36 described hereinabove),and generates responsive thereto a stimulation signal 64 conveyed by oneor more electrodes 66 to the SPG, another MTS, or other tissue.Typically, but not necessarily, feedback signal 68 comprises electricalfeedback measured by one or more of electrodes 66 and/or feedback fromother sensors on or in the patients brain or elsewhere coupled to thepatient's body. If appropriate, microprocessor 52 generates a displaysignal 60 which drives a display block 62 to output relevant data to thepatient or the patient's physician. Typically, some or all of electrodes66 are temporarily implanted in the patient (e.g., following a stroke),and are directly driven by wires connecting the external unit to theimplanted unit.

FIG. 5A is a graph schematically illustrating a mode of operation of oneor more of the devices shown in FIGS. 1-4, in accordance with apreferred embodiment of the present invention. Preferably, the effect ofthe applied stimulation is monitored by means of a temperaturetransducer at the SPG, at another MTS, or elsewhere in the head, e.g.,in the nasal cavity. As shown in FIG. 5A for a step (ON/OFF) mode ofstimulation, stimulation of the SPG or related tissue, or of anotherMTS, is initiated at a time T1, and this is reflected by a measurablerise in temperature (due to increased blood flow). Once the temperaturerises to a predetermined or dynamically-varying threshold (e.g., 37°C.), stimulation is terminated (time T2), responsive to which thetemperature falls. As appropriate, when the temperature drops to adesignated or dynamically-determined point, the stimulation isreinitiated (time T3). Preferably, suitable temperatures or otherphysiological parameters are determined for each patient so as toprovide the optimal treatment. If appropriate, control instructions mayalso be received from the patient, e.g., to initiate stimulation uponthe onset of a migraine headache.

FIG. 5B is a graph schematically illustrating a mode of operation of oneor more of the devices shown in FIGS. 1-4, in accordance with anotherpreferred embodiment of the present invention. In this embodiment, theamplitude of the waveform applied to the SPG or another MTS is variedamong a continuous set of values (S1), or a discrete set of values (S2),responsive to the measured temperature, in order to achieve the desiredperformance. It will be appreciated that other feedback parametersmeasured in the head (e.g., intracranial pressure and/or cerebral bloodflow), as well as measured systemic parameters (e.g., heart rate) andsubjective patient inputs (e.g., migraine pain=⅗) may be used inconjunction with or separately from temperature measurements, in orderto achieve generally optimal performance of the implanted apparatus.

FIG. 6 is a graph schematically illustrating a mode of operation of oneor more of the devices shown in FIGS. 1-4, in accordance with apreferred embodiment of the present invention. In this embodiment, adrug is administered to the patient at a constant rate, e.g.,intravenously, prior to the initiation of stimulation of the SPG oranother MTS at time T1. Advantageously, this prior generation ofheightened concentrations of the drug in the blood tends to providerelatively rapid transfer of the drug across the BBB and into the brain,without unnecessarily prolonging the enhanced permeability of the BBBwhile waiting for the blood concentration of the drug to reach anappropriate level. Alternatively, for some applications it is desirableto give a single injection of a bolus of the drug shortly before orafter initiation of stimulation of the SPG or another MTS. Typically,combined administration and stimulation schedules are determined by thepatient's physician based on the biochemical properties of each drugtargeted at the brain.

As used in the specification and in the claims, stimulation of an MTS tofacilitate transport of a diagnostic agent from the systemic bloodcirculation to the CNS, is to be understood as including stimulationprior to, during, and/or after administration of the agent to thesystemic circulation. For subjects in whom an MTS stimulator previouslywas implanted for therapeutic purposes, such implanted stimulator may beused for performing stimulation to facilitate a diagnosis, as describedherein.

FIG. 7 is a schematic block diagram showing circuitry forparasympathetic stimulation, which is particularly useful in combinationwith the embodiments shown in FIGS. 1A and 1B, in accordance with apreferred embodiment of the present invention. An external unit 80preferably comprises a microprocessor 82 that is powered by a battery 84and/or an AC power source. Microprocessor 82 is grounded through battery84 or through an optional ground 86.

In a typical mode of operation, an external control signal 88 is inputto microprocessor 82, along with a feedback signal 108 from one or morebiosensors 106, which are typically disposed in a vicinity of animplanted unit 100 or elsewhere on or in the patient's body. Responsiveto signals 88 and 108, microprocessor 82 preferably generates a displaysignal 89 which drives a display 90, as described hereinabove. Inaddition, microprocessor 82 preferably processes external control signal88 and feedback signal 108, to determine parameters of an output signal92, which is modulated by a modulator 94. The output therefrompreferably drives a current through an electromagnetic coupler 96, whichinductively drives an electromagnetic coupler 98 of implanted unit 100.A demodulator 102, coupled to electromagnetic coupler 98, in turn,generates a signal 103 which drives at least one electrode 104 to applycurrent to the SPG or to other tissue, as appropriate.

Preferably, biosensor 106 comprises implantable or external medicalapparatus including, for example, one or more of the following:

-   -   a blood flow sensor,    -   a temperature sensor,    -   a chemical sensor,    -   an ultrasound sensor,    -   transcranial Doppler (TCD) apparatus, laser-Doppler apparatus,    -   a systemic or intracranial blood pressure sensor (e.g.,        comprising a piezoelectric crystal fixed to a major cerebral        blood vessel, capable of detecting a sudden blood pressure        increase indicative of a clot),    -   a kinetics sensor, comprising, for example, an acceleration,        velocity, or level sensor (e.g., a mercury switch), for        indicating body dispositions such as a sudden change in body        attitude (as in collapsing),    -   an electroencephalographic (EEG) sensor comprising EEG        electrodes attached to, or implanted in, the patients head, for        indicating changes in neurological patterns, such as symptoms of        stroke or migraine,    -   a blood vessel clot detector (e.g., as described hereinbelow        with reference to FIG. 13), or    -   other monitors of physiological quantities suitable for carrying        out the objects of this or other embodiments of the present        invention.

FIG. 8 is a schematic illustration showing operational modes ofmodulator 94 and/or demodulator 102, in accordance with a preferredembodiment of the present invention. The amplitude and frequency ofsignal 92 in FIG. 7 can have certain values, as represented in the leftgraph; however, the amplitude and frequency are modulated so that signal103 has different characteristics (not necessarily those shown).

FIG. 9 is a schematic illustration of further apparatus for stimulationof the SPG or another MTS, in accordance with a preferred embodiment ofthe present invention. In this embodiment, substantially all of theprocessing and signal generation is performed by circuitry in animplanted unit 110 in the patient, and, preferably, communication with acontroller 122 in an external unit 111 is performed only intermittently.The implanted unit 110 preferably comprises a microprocessor 112 coupledto a battery 114. Microprocessor 112 generates a signal 116 that travelsalong at least one electrode 118 to stimulate the SPG or another MTS. Afeedback signal 120 from a biosensor (not shown) and/or from electrode118 is received by microprocessor 112, which is adapted to modifystimulation parameters responsive thereto. Preferably, microprocessor112 and controller 122 are operative to communicate via electromagneticcouplers 126 and 124, in order to exchange data or to change parameters.Further preferably, battery 114 is inductively rechargeable byelectromagnetic coupling.

FIG. 10A is a schematic illustration of a stimulator 150, in accordancewith a preferred embodiment of the present invention. Preferably,substantially all of the electronic components (including an electroniccircuit 158 having a rechargeable energy source) are encapsulated in abiocompatible metal case 154. An inductive coil 156 and at least oneelectrode 162 are preferably coupled to circuit 158 by means of afeed-through coupling 160. The inductive coil is preferably isolated byan epoxy coating 152, which allows for higher efficiency of theelectromagnetic coupling.

FIG. 10B is a schematic illustration of another configuration of animplantable stimulator, in accordance with a preferred embodiment of thepresent invention. Preferably, substantially all of the electroniccomponents (including an inductive coil 176 and an electronic circuit178 having a rechargeable energy source) are encapsulated in abiocompatible metal case 174. One or more feed-throughs are preferablyprovided to enable coupling between at least one electrode 182 and theelectronic circuit, as well as between inductive coil 176 and anotherinductive coil (not shown) in communication therewith.

With reference to FIGS. 10A and 10B, the energy source for electroniccircuits 158 and 178 may comprise, for example, a primary battery, arechargeable battery, or a super capacitor. For applications in which arechargeable battery or a super capacitor is used, any kind ofenergizing means may be used to charge the energy source, such as (butnot limited to) standard means for inductive charging or a miniatureelectromechanical energy converter that converts the kinetics of thepatient movement into electrical charge. Alternatively, an externallight source (e.g., a simple LED, a laser diode, or any other lightsource) may be directed at a photovoltaic cell in the electroniccircuit. Further alternatively, ultrasound energy is directed onto theimplanted unit, and transduced to drive battery charging means.

FIGS. 11 and 12 are bar graphs showing experimental results obtainedduring rat experiments performed in accordance with a preferredembodiment of the present invention. A common technique in monitoringbio-distribution of materials in a system includes monitoring thepresence and level of radio-labeled tracers. These tracers are unstableisotopes of common elements (e.g., Tc, In, Cr, Ga, and Gd), conjugatedto target materials. The chemical properties of the tracer are used as apredictor for the behavior of other materials with similarphysiochemical properties, and are selected based on the particularbiological mechanisms that are being evaluated. Typically, a patient orexperimental animal is placed on a Gamma camera, or target tissuesamples can be harvested and placed separately into a well counter. Forthe purpose of the present set of experiments which were performed, thewell counter method was chosen due to its higher sensitivity and spatialresolution. A series of experiments using 99Tc-DTPA (DTPA moleculeconjugated to a 99-Technetium isotope) were performed. The molecularweight of 99Tc-DTPA is 458 Da, its lipophilicity is negative, and itselectric charge is +1. These parameters are quite similar withpharmacological agents used in standard chemotherapy, such as tamoxifen,etoposide and irinotecan.

FIGS. 11 and 12 show results obtained using 99Tc-DTPA penetration assaysusing ordinary brain sampling techniques (FIG. 11) and peeled braintechniques (FIG. 12). The x-axis of each graph represents differentexperimental runs, and the y-axis of each graph is defined as:[(hemisphere radioactivity)/(hemisphere weight)]/[(total injectedradioactivity)/(total animal weight)]. The results obtained demonstratean average 2.5-fold increase in the penetration of 99Tc-DTPA to the ratbrain. It is noted that these results were obtained by unilateralstimulation of the SPG. The inventors believe that bilateral SPGstimulation will approximately double drug penetration, relative tounilateral SPG stimulation.

In both FIG. 11 and FIG. 12, some animals were designated as controlanimals, and other animals were designated as test animals. In eachgroup, the left and right hemispheres were tested separately, and theheight of each bar represents, for a given animal and a givenhemisphere, the normalized level of radioactivity as defined above.Thus, FIG. 11 shows results from a total of four test hemispheres andfour control hemispheres. FIG. 12 shows results from six testhemispheres and fourteen control hemispheres. The juxtaposition ofcontrol and test bars in the bar graphs is not meant to imply pairing ofcontrol and test hemispheres.

FIG. 13 is a schematic illustration of acoustic or optical clotdetection apparatus 202, for use, for example, in providing feedback toany of the microprocessors or other circuitry described hereinabove, inaccordance with a preferred embodiment of the present invention. Thedetection is preferably performed by coupling to a major blood vessel200 (e.g., the internal carotid artery or aorta) a detecting elementcomprising an acoustic or optical transmitter/receiver 206, and anoptional reflecting surface 204. Natural physiological liquids may serveas a mediating fluid between the device and the vessel. Preferably, thetransmitter/receiver generates an ultrasound signal or electromagneticsignal which is reflected and returned, and a processor evaluateschanges in the returned signal to detect indications of a newly-presentclot. Alternatively, a transmitter is placed on side of the vessel and areceiver is placed on the other side of the vessel. In either case, forsome applications, more than one such apparatus 202 are placed on thevessel, in order to improve the probability of successful clot detectionfor possible estimation of the clot's direction of motion within thevessel, and to lower the false alarm (i.e. false detection) rate.

FIG. 14 is a schematic sectional illustration of a nasal inhaler 300,for use in presenting an odorant to a subject, in accordance with apreferred embodiment of the present invention. Nasal inhaler 300preferably comprises apparatus known in the art, such as an aqueousspray nasal inhaler, a metered dose nasal inhaler, or an air-dilutionolfactometer. The odorant is stored in an odorant-storage vessel 302,and is delivered to a nasal passage using an odorant-delivery element304, such as a nasal piece. Alternatively or additionally, the odorantis presented by means of an orally-dissolvable capsule that releases theactive odorants upon contact with salivary liquids. The odorants reachthe appropriate neural structures and induce vasodilatation,vasoconstriction and/or cerebrovascular permeability changes.

FIG. 15 is a graph showing the results of an efflux study, performed inaccordance with an embodiment of the present invention. Techniquesdescribed in the following two articles, which are incorporated hereinby reference, were applied for use with this embodiment:

-   Asaba et al., “Blood brain barrier is involved in the efflux    transport of a neuroactive steroid, dehydroepiandrosterone sulfate,    via organic anion transporting polypeptide 2.” J. Neurochem. 75, pp.    1907-1916, (2000).-   Isakovic et al., “The efflux of purine nucleobases and nucleosides    from the rat brain.” Neuroscience Letters 318, pp. 65-68, (2002).

Male Wistar rats (280-300 g; Harlan) were used. Six rats were in anexperimental group, and six rats were in a control group. A BEI (brainefflux index) study was performed according to the method described inan article by Kakee et al., “Brain efflux index as a novel method ofanalyzing efflux transport at the blood brain barrier.” J. Pharmacol.Exp. Ther. 277, 1550-1559. (1996), which is incorporated herein byreference. Rats were anesthetized by intraperitoneal administration ofPentobarbital, and then mounted on a stereotaxic frame. A burr hole wasmade 5.5 mm lateral and 0.2 mm anterior to the bregma, and a fineinjection needle was advanced to a depth of 4.5 mm. Then, 0.50 ml of[3H]PNA (150,000 disintegrations per minute (dpm), 0.5′-CCGCTCCG-3′, MW.2122) dissolved in extracellular fluid (ECF) buffer (122 mM NaCl, 25 mMNaHCO3, 10 mM D-glucose, 3 mM KCl, 1.4 mM CaCl2, 1.2 mM MgSO4, 0.4 mMK2HPO4, 10 mM HEPES, pH 7.4) was administered over 1 min using a 5.0-mlmicrosyringe (Hamilton, Reno, Nebr., U.S.A.) fitted with a fine needleat a depth of 4.5 mm from the surface of the scalp (that is, in theparietal cortex area 2 (Par2) region). At the end of the experiment (60min), an aliquot of CSF was collected from the cisterna magna, usingtechniques described in Kakee et al., 1996. The whole brain wassubsequently isolated, and the left cerebrum, right cerebrum, andcerebellum were isolated. After weighing, tissue samples were dissolvedin 1 ml of 2 M NaOH at 50° C. for 3 h and then were mixed with 4 ml ofscintillation cocktail. The associated radioactivity was measured in aliquid scintillation counter equipped with an appropriate crossovercorrection of 3H (LS-6500; Beckman, Fullerton, Calif., U.S.A.).

The SPG stimulation protocol included cycling between on-periods,lasting 90 seconds, and off-periods, lasting for 60 seconds. During eachon-period, a 5 volt, 10 Hz signal was applied to the SPG, each pulsehaving a pulse width of 1 ms. The signal was applied using a concentricbipolar electrode, both poles of the electrode being inserted slightlyinto the SPG.

FIG. 15 clearly shows the increased clearance of the injected tracerfrom the animals that received electrical SPG stimulation, compared tothe clearance in the non-stimulated (i.e., control) animals. The errorbars represent one standard deviation. No electrodes were inserted intothe SPG of the control animals.

FIG. 16 is a graph showing the results of an experiment performed inaccordance with an embodiment of the present invention. Four beagleswere in a control (non-stimulated) group, and four beagles were in astimulated group. No electrodes were applied to the SPG of the animalsof the control group. At time zero, a solution of 10 kDa FITC-dextrantracer was administered intravenously, and, at the same time, SPGstimulation was initiated. Administration of the dextran was performedcontinuously over a 20 minute period, and SPG stimulation continued for30 minutes (i.e., for 10 minutes after termination of the dextranadministration). The SPG stimulation protocol included cycling betweenon-periods, lasting 90 seconds, and off-periods, lasting for 60 seconds.During each on-period, a 6 volt, 10 Hz signal was applied to the SPG,each pulse having a pulse width of 1 ms. The signal was applied using aconcentric bipolar electrode, both poles of the electrode being insertedslightly into the SPG.

After termination of the SPG stimulation (or equivalent time period inthe control group), each animal was sacrificed. Concentrations ofdextran in various parts of each beagle's brain were measured. In thecontrol group, concentrations in the left half and the right half weremeasured separately, such that the control results shown in FIG. 16represent n=8, from four animals. In the experimental group, fouranimals were used. For each experimental animal, only one sample wastaken from each brain region, ipsilateral to the stimulation (thus n=4).

FIG. 16 shows results from six brain regions known to be regulated tosome extent by the SPG (the frontal cortex, the temporal cortex, frontalwhite matter, the olfactory bulb, the striatum, and the hippocampus).FIG. 16 also shows dextran concentrations measured in the pons, aportion of the brain regulated by the otic ganglion (and substantiallynot by the SPG). Notably, the results of this experiment show thatdextran concentrations in each of the six regions regulated by the SPGwere significantly higher in the SPG-stimulated group than in thecontrol group. The high concentration of the dextran tracer (a largemolecule), indicates that BBB permeability was substantially increasedas a result of the SPG stimulation, in the brain regions regulated bythe SPG. Also notable is the almost exact equivalence between thedextran levels in the pons of the SPG-stimulated animals and in the ponsof the control animals. The contrast between:

-   -   (a) the equivalence of the experimental and control groups, in a        non-SPG-regulated brain tissue, and    -   (b) the significant differences between the experimental and        control groups in the SPG-regulated brain tissues, is a strong        indication that the displayed significant effect of the        experimental protocol shown in FIG. 16 is a result of modulating        the functioning of the SPG and its control over BBB permeability        in certain portions of the brain.

In addition to the results shown in FIG. 16 and described hereinabove,the inventor additionally assessed the concentration of the dextrantracer in temporal muscle of the animals in the SPG-stimulated group andin the control group. It is noted that temporal muscle, being outside ofthe brain, has no protection from the BBB. The results show that thedextran concentrations rose to high and essentially equivalent values inthe temporal muscle of the animals in both the SPG-stimulated group andthe control group. This, in combination with the pons data, shows thatSPG stimulation as provided herein only produced a measured effect onbrain tissue that is regulated by the SPG.

FIG. 17 shows results from an experiment which included one hour ofcontinuous SPG stimulation in five rats, in accordance with anembodiment of the present invention. Prior to the initiation of SPGstimulation, cerebral blood flow (CBF) was measured, and thismeasurement provided a baseline for subsequent CBF measurements. CBF wascontinuously recorded throughout the hour of SPG stimulation, andcontinued to be recorded for 30 minutes after the stimulation ceased.SPG stimulation protocols were identical to those described hereinabovewith reference to FIG. 15.

Three bars are shown in FIG. 17. The left bar represents the averageblood flow change 20 minutes after SPG stimulation was initiated. Themiddle bar shows average blood flow change 40 minutes after stimulationwas initiated, and the right bar shows average blood flow change 20minutes after the termination of SPG stimulation. From this figure, itis evident that during SPG stimulation, a CBF increase of around 50%(i.e. 150% of original blood flow level) is measured. This increase incerebral blood flow is believed to be associated with improved metabolicstate of brain tissue supplied by the CBF, as supported by other datacollected by the inventor (not shown).

FIG. 18 is a schematic illustration of an implantable stimulator 400 forstimulation of an MTS, in accordance with an embodiment of the presentinvention. Stimulator 400 is preferably implanted adjacent to orbitalcavity 408 of a subject. At least one electrode 402 extends from thestimulator to at least one of: an anterior ethmoidal nerve 404 and aposterior ethmoidal nerve 406, which are modulation target sites.Stimulator 400 is preferably implanted through an incision made in theupper edge of the eyelid (not shown).

In an embodiment of the present invention, an odorant is presented to anair passage of a patient, such as a nasal cavity or the throat, so as toincrease transport of a diagnostic agent across the BBB from thesystemic blood circulation to the CNS, in order to facilitate adiagnosis of a CNS condition. Alternatively or additionally, an odorantis similarly presented in order to enhance transport of a biochemicalagent from the CNS to a non-CNS tissue, such as the systemic bloodcirculation, in order to facilitate a diagnosis of a CNS condition.

In an embodiment of the present invention, stimulation of the MTS isachieved by applying a neuroexcitatory agent to the MTS. Suitableneuroexcitatory agents include, but are not limited to acetylcholine andurocholine. For some applications, the MTS is stimulated by applying aneuroinhibitory agent, such as atropine, hexamethonium, or a localanesthetic (e.g., lidocaine).

In an embodiment of the present invention, stimulation of the MTS isachieved by applying mechanical stimulation to the MTS, e.g., vibration.

Embodiments of the present invention have many medical applications. Forexample, chemotherapeutic drugs need to pass into cerebral tissue inorder to treat brain tumors. Most of the chemotherapeutic drugs havemolecular weights of 200-1200 Da, and thus their transport through theblood-brain barrier (BBB) is highly restricted. To overcome theimpedance of the BBB, an intracarotid infusion of high osmotic load hasbeen used in the prior art in order to open the tight junctions of theBBB for a very short period (e.g., 25 minutes), during which themedications are given. This procedure is not simple—it is invasive,requires general anesthesia, requires subsequent intensive care, and isin any case relatively expensive. For these reasons, such intracarotidinfusions are used only in very few healthcare facilities, even thoughsome reports claim a substantial improvement in life expectancy inpatients receiving chemotherapy in this manner.

Preferably, embodiments of the present invention which facilitateincreased trans-BBB drug delivery, and therefore more efficientchemotherapy, also enable a reduction or elimination of the need forradiotherapy. It is noted that such irradiation of the brain isindicated in the literature to be a significant cause of long-termcognitive and other deficits.

The better delivery of drugs, as provided in accordance with a preferredembodiment of the present invention, is also a factor in the treatmentof other disorders, such as Parkinson's disease, Alzheimer's disease,and other neurological diseases. For some applications, the trans-BBBdelivery of various growth factors is facilitated using the techniquesdescribed herein. Growth factors are typically large molecules thatstimulate the growth of neurons, and may be used to treat degenerativedisorders, such as Parkinson's disease, Alzheimer's disease, and MotorNeuron Diseases (e.g., Lou Gehrig's disease).

Another preferred application of the present invention includesfacilitating drug delivery across the BBB in order to treat inflammationin the brain, e.g., for cases of infectious diseases of the brain inimmunocompromised patients. Similarly, medications to treat AIDS may bemore effectively administered to sites in the brain through the BBB,when appropriate, through the use of methods and apparatus describedherein. A further application of some embodiments of the presentinvention includes the delivery through the BBB of viruses that areagents of gene therapy (e.g., for treating Parkinson's disease).Similarly, methods and apparatus described herein may be used formetabolic disorders of the brain, such as GM2 gangliosidosis.

Another aspect of some preferred embodiments of the invention relates tothe modulation of cerebral blood flow. Roughly 750,000 Americans sufferstrokes each year. Stroke is the United States' third leading cause ofdeath, killing about 160,000 Americans every year. More than 3 millionpeople in the United States have survived strokes, of whom more than 2million suffer crippling paralysis, speech loss and lapses of memory.About 85% of strokes are ischemic, i.e., a blood vessel is occluded andits territory is deprived of oxygen supply. A cerebral region that istotally deprived of blood supply is surrounded by a second region ofpartial lack of supply, whose vitality is at risk. This second region isone of the main targets of some embodiments of the invention—stimulationof the SPG will dilate its vessels and significantly improve thatregion's likelihood of survival. If the intervention is given earlyenough in the event (e.g., a few hours post-stroke), it might help alsothe core region of the stroke, as the thrombus is not yet organized, anddilation of the vessels may reintroduce blood supply to the tissue.Alternatively, SPG stimulation may allow the clot to move from a bigvessel to a small vessel, and thus deprive blood supply only from a muchsmaller volume of the brain (which would, in any case, have probablybeen deprived of blood supply had the clot remained in place).

Population-based studies have shown that about 5% of men and 16% ofwomen suffer migraine attacks. Over 80% of these people suffer somedegree of headache-related disability. Parasympathetic block (incontrast to stimulation) is known to cause vasoconstriction. Anembodiment of the present invention uses electrical means to induce thevasoconstrictive effect and treat migraine. For example, it may usetechniques to block nerve messaging, such as applying a slowly-varyingvoltage, or in some cases, a constant level DC voltage.

Alzheimer's disease is becoming a major source of disability andfinancial load with the increase in life expectancy. In recent years,vascular factors have been considered prominent in the pathophysiologyof the disease. Current therapy is generally concentrated along oneline—cholinomimetic medications, which can, at most, slow down thedeterioration of cognitive function in patients. SPG stimulation, asprovided in accordance with a preferred embodiment of the presentinvention, is believed to increase blood flow and oxygen supply to thebrain, and therefore help these patients. For this use, permanentstimulators may be implanted in the nasal cavity, for long-termintermittent stimulation.

In general, it is believed that substantially all pharmacologicaltreatments aimed at cerebral cells for neurological and psychiatricdisorders are amenable for use with these embodiments of the presentinvention. In particular, this embodiment may be adapted for use in thetreatment of disorders such as brain tumors, epilepsy, Parkinson'sdisease, Alzheimer's disease, multiple sclerosis, schizophrenia,depression, stress, anxiety, disorders requiring the administration ofvarious growth factors, and other CNS disorders that are directly orindirectly affected by changes in cerebral blood flow or by BBBpermeability changes.

Alternatively or additionally, a method is provided for increasing orreducing cortical blood flow and/or inducing or inhibiting vasodilation(even in the absence of BBB permeability changes) by presenting anodorant to an air passage of a patient, such as a nasal cavity or thethroat, for treatment of a condition. Patients with the aforementioneddisorders and other disorders are generally helped by vasodilation andthe resultant improvement in oxygen supply to neurons and other tissue.For some applications, this treatment is given on a long-term basis,e.g., in the chronic treatment of Alzheimer's patients. For otherapplications, the treatment is performed on a short-term basis, e.g., tominimize the damage following an acute stroke event and initiateneuronal and therefore functional rehabilitation. Alternatively oradditionally, the method provided above can be used for diagnosticpurposes or in conjunction with other diagnostic methods and/orapparatus known in the art, in order to enhance diagnostic results,reduce procedure risk, reduce procedure time, or otherwise improve suchdiagnostic procedures and/or diagnostic results. For example, methodsand apparatus described herein may be used to increase the uptake intothe brain of a radio-opaque material, in order to facilitate a CT scan.

In a preferred embodiment of the present invention, stimulation of theSPG may be performed using direct galvanic contact, indirectelectromagnetic induction, photonic excitation, chemical excitation,mechanical excitation and other methods or combinations thereof, whichare known in the art of neural stimulation. Stimulation of the SPG maybe performed directly on the SPG, or the nerves connected directly orindirectly with the SPG, e.g., via reflex arc.

In a preferred embodiment of the present invention, techniques describedherein are applied in combination with methods and apparatus describedin PCT Application IL 01/00402, filed May 7, 2001, entitled, “Method andapparatus for stimulating the sphenopalatine ganglion to modifyproperties of the BBB and cerebral blood flow,” U.S. Provisional PatentApplication 60/364,451, filed Mar. 15, 2002, entitled, “Applications ofstimulating the sphenopalatine ganglion (SPG),” U.S. Provisional PatentApplication 60/368,657, filed Mar. 28, 2002, entitled, “SPGstimulation,” and/or U.S. Provisional Patent Application 60/376,048,filed Apr. 25, 2002, entitled, “Methods and apparatus for modifyingproperties of the BBB and cerebral circulation by using theneuroexcitatory and/or neuroinhibitory effects of odorants on nerves inthe head,” all of which are assigned to the assignee of the presentinvention and are incorporated herein by reference.

The better delivery of drugs, as provided in accordance with preferredembodiments of the present invention, is an important factor in thetreatment of various disorders, such as Parkinson's disease, Alzheimer'sdisease, and other neurological diseases. For some applications, thetrans-BBB delivery of various growth factors is facilitated using thetechniques described herein. Growth factors are typically largemolecules that stimulate the growth of neurons, and, in accordance witha preferred embodiment of the present invention, are used to treatdegenerative disorders, such as Parkinson's disease, Alzheimer'sdisease, and Motor Neuron Diseases (e.g., Lou Gehrig's disease).

Alzheimer's disease is becoming a major source of disability andfinancial load with the increase in life expectancy. In recent years,vascular factors have been considered prominent in the pathophysiologyof the disease. Current therapy is generally concentrated along oneline—cholinomimetic medications, which typically, at most, slow down thedeterioration of cognitive function in patients. SPG stimulation, asprovided in accordance with preferred embodiments of the presentinvention, typically increases blood flow and oxygen supply to thebrain, and therefore help these patients. For this use, permanentstimulators may be implanted in the nasal cavity, for long-termintermittent stimulation. In a preferred embodiment, the delivery ofcholinomimetic medications is facilitated by SPG stimulation.

Apart from molecular parameters, the permeability of the BBB and activetransport mechanisms, a major determinant of molecular transport acrossthe BBB is their concentration gradient—between the CNS and the cerebralcirculation. In cases where a compound has a higher concentration in thebrain than in the cerebral circulation, opening of the BBB, preferably,but not necessarily, using techniques described herein leads to anincreased net transport of that compound from the CNS into thecirculation. In a preferred embodiment, this technique is used tofacilitate a diagnosis, e.g., by enhancing permeability of the BBB,taking a blood sample, and testing the blood sample for increased levelsof the compound.

In a preferred embodiment of the present invention, parasympatheticfibers associated with the SPG are stimulated, preferably by usingelectrical stimulation and/or odorant presentation techniques describedherein, thereby rendering the BBB permeable to certain compounds in theCNS. One or more of such compounds are then analyzed by analyzing theblood of the patient. By testing such compounds that are indicative ofthe presence of AD, AD is diagnosed. Advantageously, such a testingprocedure is minimally invasive. Alternatively or additionally,molecular passage is increased to another body compartment and/or fluid,such as plasma, serum, ascites, or cerebrospinal fluid.

Moreover, in accordance with a preferred embodiment of the presentinvention, a controlled, reversible suppression of the impedance of theBBB is useful as a stand-alone treatment, when said suppressionfacilitates clearance of neurotoxic compounds, such as β-Amyloid, tau,PS1, and PS2, from the CNS into the systemic circulation. Once in thesystemic circulation, these neurotoxic compounds may be metabolized andremoved from the body with greater ease and with fewer side effects,compared to effects that accompany their presence in the CNS.

The following examples demonstrate selected therapeutic and diagnosticapplications of SPG stimulation in the management of Alzheimer'sdisease. It should be appreciated by those of skill in the art, that thefollowing examples are set forth for demonstrative purposes. However,those of skill in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentsdisclosed and still obtain a like or similar result without departingfrom the spirit and scope of the invention. The following descriptionrelates to specific embodiments for stimulation of the SPG and relatedneural structures, possible system configurations for the stimulatordevice, variations or combinations of the therapeutic and diagnosticmodalities that accompany SPG stimulation and complementary explanationfor the various mechanisms of actions of such a system for ADmanagement. Furthermore, the methods described herein may be eitherdirectly, or indirectly applicable for the management of other CNSdisorders, such as Parkinson's disease, epilepsy, ALS, MS and more. Allreferences cited herein, including articles, patents, and publishedpatent applications, are incorporated herein by reference.

EXAMPLE 1 Therapeutics (Glutamate Inhibitors)

Excitotoxicity is related to excessive activation of glutamate receptorswhich results in neuronal cell death. The physiological function ofglutamate receptors is the mediation of ligand-gated cation channelswith the concomitant influx of calcium, sodium and potassium throughthis receptor-gated channel. The influx of these cations is essentialfor maintaining membrane potentials and the plasticity of neurons whichin itself plays a pivotal role in cognitive function of the centralnervous system (Li, H. B. et al., Behav. Brain Res. 83: 225-228, 1997;Roesler, R. et al., Neurology 50: 1195, 1998; Wheal, H. V. et al., Prog.Neurobiol. 55: 611-640, 1998; Wangen, K et al., Brain Res. 99: 126-130,1997). Excitotoxicity plays an important role in neuronal cell deathfollowing acute insults such as hypoxia, ischemia, stroke and trauma,and it also plays a significant role in neuronal loss in AIDS dementia,epilepsy, focal ischemia (Coyle, J. T. et al., Science 262: 689-695,1993). Neurodegenerative disorders, such as Huntington's disease (HD),Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophiclateral sclerosis (ALS), are characterized by the progressive loss of aspecific population of neurons in the central nervous system. Growingevidence suggests that glutamate-mediated excitotoxicity may be a commonpathway which contributes to neuronal cell death in a wide range ofneurological disorders (Coyle, J. T. et al., Science 262: 689-695,1993). The molecular mechanisms of excitotoxicity-mediated neuronal celldeath remains obscure. Over-production of free radicals that lead toimpairment of mitochondrial function is the most widely held hypothesis(Beal, M. F. et al., Ann. Neurol. 38: 357-366, 1995; Coyle, J. T. etal., Science 262: 689-695, 1993). However, it is unclear in theliterature whether the increase of free radicals is the precursor thatinitiates neuronal degeneration or, rather, a subsequent consequence ofneuronal degeneration. Interestingly, administration of antioxidants isreported as having little neuroprotective effect in patients sufferingfrom various neurodegenerative diseases (Shults, C. W. et al., Neurology50: 793-795, 1998). Thus, some other mechanism(s) must exist forexcitotoxicity-induced neuronal cell death.

A potential treatment modality for AD is the systemic administration ofa JNK (c-Jun amino-terminal kinase) or MLK (Mixed lineage kinase)apoptosis inhibitor as a means for preventing AD-related apoptosis ofbrain cells. However, without the use of the techniques describedherein, achieving a therapeutic concentration of such an inhibitor inthe CNS may be accompanied by undesired dose-related side effects.Advantageously, the use of techniques described herein for enhancingdrug delivery to the CNS typically enables the achievement oftherapeutic results at lower dosages, which, in turn, lowers the risk ofdose-related side effects.

In a preferred embodiment of the present invention, the therapeutic orprophylactic administration of such inhibitors is enhanced bystimulation of the SPG and/or its related neuroanatomical structures, byusing electrical stimulation, odorant presentation, and/or other meansfor stimulating the SPG or for modulating permeability of the BBB.

EXAMPLE 2 Therapeutics β/γ Secretase Inhibitors

In a preferred embodiment of the present invention, methods fortreatment of Alzheimer's disease target the formation of β-amyloidthrough the enzymes involved in the proteolytic processing of β-amyloidprecursor protein. Compounds that inhibit β or γ secretase activity,either directly or indirectly, are used, in accordance with thisembodiment, to control the production of β-amyloid. Advantageously,compounds that specifically target γ secretases, could control theproduction of β-amyloid. Typically, such inhibition of β or γ secretasesreduces production of Aβ, which, in turn, reduces or prevents theneurological disorders associated with Aβ protein.

Compelling evidence accumulated during the last decade revealed that Aβis an internal polypeptide derived from a type I integral membraneprotein, termed b amyloid precursor protein (APP). P APP is normallyproduced by many cells both in vivo and in cultured cells, derived fromvarious animals and humans. Aβ is derived from cleavage of β APP by asyet unknown enzyme (protease) system(s), collectively termed secretases.

The existence of at least four proteolytic activities has beenpostulated. They include β secretase(s), generating the N-terminus ofAβ, a secretase(s) cleaving around the 16/17 peptide bond in Aβ, and γsecretases, generating C-terminal Aβ fragments ending at position 38,39, 40, 42, and 43 or generating C-terminal extended precursors whichare subsequently truncated to the above polypeptides.

Several lines of evidence suggest that abnormal accumulation of Aβ playsa key role in the pathogenesis of AD. First, Aβ is the major proteinfound in amyloid plaques. Second, Aβ is neurotoxic and may be causallyrelated to neuronal death observed in AD patients. Third, missense DNAmutations at position 717 in the 770 isoform of P APP can be found inaffected members but not unaffected members of several families with agenetically determined (familiar) form of AD. In addition, several otherβ APP mutations have been described in familiar forms of AD. Fourth,similar neuropathological changes have been observed in transgenicanimals overexpressing mutant forms of human β APP. Fifth, individualswith Down's syndrome have an increased gene dosage of β APP and developearly-onset AD. Taken together, these observations strongly suggest thatAβ depositions may be causally related to the AD.

It is hypothesized by the inventors that inhibiting the production of Aβinhibits neurological degeneration by controlling the formation ofamyloid plaques, reducing neurotoxicity and, generally, mediating thepathology associated with Aβ production. One method of treatmentpreferred by the inventors is based on drugs that inhibit the formationof Aβ in vivo, administered in combination with techniques for SPGstimulation described herein.

Methods of treatment preferably target the formation of Aβ through theenzymes involved in the proteolytic processing of P amyloid precursorprotein. Compounds that inhibit β or γ secretase activity, eitherdirectly or indirectly, could control the production of Aβ.Advantageously, compounds that specifically target γ secretases couldcontrol the production of Aβ. Such inhibition of p or γ secretases couldthereby reduce production of Aβ, which, in turn, could reduce or preventthe neurological disorders associated with Aβ protein.

U.S. Patent Application Publication 2002/0055501 to Olson et al.describes pharmaceutical compositions and methods of use of suchcompounds, which inhibit the processing of amyloid precursor proteinand, more specifically, inhibit the production of Aβ-peptide, therebyacting to prevent the formation of neurological deposits of amyloidprotein.

The efficacy of administration of pharmaceutical agents that inhibit theprocessing of amyloid precursor protein into P-amyloid is typicallysubstantially increased when used in conjunction with the techniques ofSPG stimulation described herein.

In a preferred embodiment of the present invention, the therapeutic orprophylactic administration of such compounds targeting production of Aβis enhanced by stimulation of the SPG and/or its related neuroanatomicalstructures, by using electrical stimulation, odorant presentation,and/or other means for stimulating the SPG or for modulatingpermeability of the BBB.

EXAMPLE 3 Therapeutics (NMDA-Receptor Blocker)

U.S. Patent Application Publication 2002/0035145 to Tsai et al.,describes a method to treat various neuropsychiatric disorders,including Alzheimer's disease. Their description relates thatneuropsychiatric disorders characterized by a deficit inneurotransmission via the NMDA receptor can be alleviated by a compoundthat acts as an agonist of the glycine site on the NMDA receptor or aninhibitor of glycine uptake. The compound is either a partial agonistsuch as D-cycloserine, which can be used at a dosage of 105-500 mg, or afull agonist (e.g., D-serine or D-alanine) that is selective for theNMDA receptor (compared to the inhibitory glycine receptor and otherreceptors), or a glycine uptake inhibitor (e.g., N-methylglycine). Theydescribe methods for treating neuropsychiatric disorders in patients(i.e., humans). Examples of disorders that can be treated by the methodsthey describe include schizophrenia, Alzheimer's disease, autism,depression, benign forgetfulness, childhood learning disorders, closedhead injury, and attention deficit disorder. The methods entailadministering to a patient diagnosed as suffering from such aneuropsychiatric disorder a pharmaceutical composition that contains atherapeutically-effective amount of an agonist of the glycine site ofthe NMDA receptor or a glycine uptake inhibitor, which agonist isrelatively selective for (a) the glycine site of the NMDA receptor,compared with (b) the inhibitory glycine receptor and other receptors.The pharmaceutical composition may include, for example, (i) atherapeutically effective amount of D-alanine (wherein thepharmaceutical composition is substantially free of D-cycloserine)and/or (ii) a therapeutically effective amount of D-serine, and/or (iii)D-cycloserine in an amount of 105-500 mg, and/or (iv) a therapeuticallyeffective amount of N-methylglycine.

U.S. Patent Application Publication 2001/0051633 to Bigge et al.,describes a subtype-selective NMDA receptor ligands and the use thereoffor treating or preventing neuronal loss associated withneurodegenerative diseases including Alzheimer's disease by treating orpreventing the adverse consequences of the overstimulation of theexcitatory amino acids.

U.S. Patent Application Publication 2001/0047014 to Alanine et al.,describes a compound of the formula 1 its R,R-, S,S-enantiomers andracemic mixtures, also suitable for the treatment of Alzheimer'sdisease.

In a preferred embodiment of the present invention, the therapeutic orprophylactic administration of such compounds described in this example(Example 3), and/or the diagnostic use thereof, is enhanced bystimulation of the SPG and/or its related neuroanatomical structures, byusing electrical stimulation, odorant presentation, and/or other meansfor stimulating the SPG or for modulating permeability of the BBB.

EXAMPLE 4 Therapeutics (Cholinesterase Inhibitors)

U.S. Patent Application Publication 2002/0028834 to Villalobos et al.,describes the use of cholinesterase inhibitors for enhancing memory inpatients suffering from dementia and Alzheimer's disease. It is knownthat acetylcholinesterase inhibitors are effective in enhancingcholinergic activity and useful in improving the memory of Alzheimer'spatients. By inhibiting acetylcholinesterase enzyme, these compoundsincrease the level of the neurotransmitter acetylcholine in the brainand thus enhance memory. Becker et al., cited hereinabove, report thatbehavioral changes following cholinesterase inhibition appear tocoincide with predicted peak levels of acetylcholine in the brain. Theyalso discuss the efficacy of three known acetylcholinesteraseinhibitors, physostigmine, metrifonate, and tetrahydroaminoacridine.

In a preferred embodiment of the present invention, the therapeutic orprophylactic administration of such cholinesterase inhibitors isenhanced by stimulation of the SPG and/or its related neuroanatomicalstructures, by using electrical stimulation, odorant presentation,and/or other means for stimulating the SPG or for modulatingpermeability of the BBB.

EXAMPLE 5 Therapeutics (Direct Stimulation of Neural Regeneration)

There are continuous efforts to use a Nerve Growth Factor (NGF) as astimulant of neural regeneration, thus potentially slowing degenerativeprocesses, or even reversing neural damage. (NGF belongs to a largefamily of neural growth factors, including BDNF, IGF, GDNF and otheractive stimulants of neural regeneration. However, for the purpose ofthe present patent application, the term NGF shall be used to representany such compound, or combinations thereof). Therefore, growth factortherapy for AD is considered a potentially curative approach of diseasemanagement. However, such an approach still has to overcome thechallenge of administering growth factor in adequate amounts, preferablyover a continuous period of time, into the CNS. In the prior art, theBBB is generally considered impermeable to high molecular weightcompounds, and thus systemic administration of growth factor, withoutusing the techniques described herein, is not generally considered atreatment option for a patient with a functional BBB.

Because the BBB is generally considered in the prior art to beimpermeable to high molecular weight compounds, invasive methods havebeen developed to enable NGF to reach a patient's brain. For example, apossible method for AD therapy, currently being tested in clinicaltrials, uses gene therapy techniques for the in-situ production ofgrowth factors. This method involves brain surgery, where a patient'sown cells are genetically modified to produce the NGF. The patient'scells, called “fibroblasts,” are obtained from skin biopsies. Thefibroblasts are genetically modified in vitro and are then implantedinto either 5 or 10 locations in the patient's brain. The eventual goalof this research effort is to determine whether NGF produced by thecells implanted into the brain can prevent the death of some nerve cellsthat are affected in Alzheimer's disease, and enhance the function ofsome remaining brain cells.

In animal studies, fibroblasts genetically modified to produce NGF havebeen shown to prevent the death of certain nerve cells in the brain.This effectiveness has been shown in both the rat brain and the monkeybrain. The genetically-modified cells prevent cell death after injury,and prevent cell atrophy that is a natural consequence of aging inprimates.

A straightforward approach to circumventing the BBB would be to piercethe meninges and directly administer growth factors into the CNS. Thistechnique, however, has several drawbacks. First, it puts the patient ina continuous risk of inflammatory brain processes. Second, directinfusion into the brain is usually very localized, and therefore itseffectiveness is limited to the close vicinity of the administrationtip, especially where the active molecule is of high molecular weight,making it less mobile. It is therefore clear that a relatively safemethod of transiently opening the BBB to large molecular weightmolecules, such as that described herein, could make nerve growthfactors a compound of choice for the treatment of AD.

In a preferred embodiment of the present invention, the therapeutic orprophylactic administration of nerve growth factor is enhanced bystimulation of the SPG and/or its related neuroanatomical structures, byusing electrical stimulation, odorant presentation, and/or other meansfor stimulating the SPG or for modulating permeability of the BBB.

U.S. Patent Application Publication 2002/0040052 to Ito et al.,describes a method for extending neurites of neurocytes without any sideeffects, and a method for preventing and/or treating neurodegenerationdiseases using compositions having neurite extending effect. Thisinvention is described as being necessary because the more direct methodof administering NGF directly suffers from several limitations:“However, an NGF is a protein having a molecular weight of 13000 in theform of monomer and 26000 in the form of dimer, so that it cannot passthrough the blood-brain barrier. Therefore, in order to treat disordersof central function, NGFs are required to be administratedintraventricularly. Moreover, it is difficult to prepare NGFs in largequantities. In these respects, there are many problems about the use ofNGF itself. As a result, it is very difficult to use NGF itselfclinically.”

EXAMPLE 6 Therapeutics (Indirect Stimulation of Neural Regeneration)

One of the characteristics of Alzheimer's disease (AD) is loss ofpresynaptic markers such as synaptophysin. Synaptophysin decreases inneurodegenerative disorders along with a decline in neurotransmission.Synaptophysin: (i) is a synaptic vesicle-associated integral membraneprotein (molecular weight about 38 kDa), (ii) acts as a specific markerfor the presynaptic terminal, and (iii) is involved in neuronaltransmission (Scheller, R. H., “Membrane Trafficking in the PresynapticNerve Terminal,” Neuron 14: 893-897, 1995). A combination ofneurotrophic factors is most effective in providing optimal trophicsupport for compromised neuron functions, including neurotransmission(Rathbone M. P. et al., “AIT-082 as a potential neuroprotective andregenerative agent in stroke and central nervous system injury,” Exp.Opin. Invest. Drugs. 8: 1255-12652, 1999). Multiple neurotrophic factorsmay synergistically regulate synaptophysin levels in a manner that canlead to increased neurotransmission and improved neuronal function.

Pharmaceutical agents that increase synaptophysin synthesis and/orsecretion, decrease its metabolism, increase its release or improve itseffectiveness may also be of benefit in reversing the course ofneurological diseases including neurodegenerative diseases, such asAlzheimer's disease, and improve function in neurodevelopmentaldisorders, such as Down's syndrome. U.S. Patent Application Publication2002/0040032 to Glasky et al. describes a method of increasing thesynthesis and/or secretion of synaptophysin, comprising administering toa patient with a neurological disease or a patient at risk of developinga neurological disease an effective quantity of a purine derivative oranalogue, a tetrahydroindolone derivative or analogue, or a pyrimidinederivative or analogue. If the compound is a purine derivative, thepurine moiety can be guanine or hypoxanthine.

Therefore, there exists a need for methods that can stimulate thesynthesis and/or secretion of synaptophysin in patients withneurological diseases, including neurodegenerative diseases such as ADand neurodevelopmental disorders such as Down's syndrome, in order topreserve, restore or improve neuronal transmission capability in suchpatients. Preferably, these methods are combined with methods thatenable active compounds to cross the BBB, making combined therapy moreefficient. These methods are suitable for use with compounds orpharmaceutical compositions that can stimulate nerve growth orregeneration in patients with neurological diseases, includingneurodegenerative diseases such as AD and neurodevelopmental disorderssuch as Down's syndrome, thus reversing the course of the disease.

In a preferred embodiment of the present invention, the therapeutic orprophylactic administration of compounds affecting synaptophysin, and/orthe diagnostic use thereof, is enhanced by stimulation of the SPG and/orits related neuroanatomical structures, by using electrical stimulation,odorant presentation, and/or other means for stimulating the SPG or formodulating permeability of the BBB.

U.S. Patent Application Publication 2002/0019519 to Bingham et al.describes the use of KIAA0551 polypeptides and polynucleotides in thedesign of protocols for the treatment of various neurological disorders,among which is AD.

In a preferred embodiment of the present invention, the therapeutic orprophylactic administration of KIAA0551 polypeptides andpolynucleotides, and/or the diagnostic use thereof, is enhanced bystimulation of the SPG its related neuroanatomical structures, by usingelectrical stimulation, odorant presentation, and/or other means forstimulating the SPG or for modulating permeability of the BBB.

EXAMPLE 7 Therapeutics (Antioxidants)

A number of diseases and disorders are thought to be caused by or to beassociated with alterations in mitochondrial metabolism and/orinappropriate induction or suppression of mitochondria-related functionsleading to apoptosis. These include, by way of example and notlimitation, chronic neurodegenerative disorders such as Alzheimer'sdisease (AD) and Parkinson's disease (PD); auto-immune diseases;diabetes mellitus, including Type I and Type II; mitochondria associateddiseases, including but not limited to congenital muscular dystrophywith mitochondrial structural abnormalities, fatal infantile myopathywith severe mtDNA depletion and benign “later-onset” myopathy withmoderate reduction in mtDNA, MELAS (mitochondrial encephalopathy, lacticacidosis, and stroke) and MIDD (mitochondrial diabetes and deafness);MERFF (myoclonic epilepsy ragged red fiber syndrome); arthritis; NARP(Neuropathy; Ataxia; Retinitis Pigmentosa); MNGIE (Myopathy and externalophthalmoplegia; Neuropathy; Gastro-Intestinal; Encephalopathy), LHON(Leber's; Hereditary; Optic; Neuropathy), Kearns-Sayre disease;Pearson's Syndrome; PEO (Progressive External Ophthalmoplegia); Wolframsyndrome DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy,Deafness); Leigh's Syndrome; dystonia; schizophrenia; andhyperproliferative disorders, such as cancer, tumors and psoriasis.

According to generally accepted theories of mitochondrial function,proper ETC respiratory activity requires maintenance of anelectrochemical potential (ATm) in the inner mitochondrial membrane by acoupled chemiosmotic mechanism. Conditions that dissipate or collapsethis membrane potential, including but not limited to failure at anystep of the ETC, may thus prevent ATP biosynthesis and hinder or haltthe production of a vital biochemical energy source. Altered ordefective mitochondrial activity may also result in a catastrophicmitochondrial collapse that has been termed “mitochondrial permeabilitytransition” (MPT). In addition, mitochondrial proteins such ascytochrome c and “apoptosis inducing factor” may dissociate or bereleased from mitochondria due to MPT (or the action of mitochondrialproteins such as Bax), and may induce proteases known as caspases and/orstimulate other events in apoptosis (Murphy, Drug Dev. Res. 46: 18-25,1999).

Defective mitochondrial activity may alternatively or additionallyresult in the generation of highly-reactive free radicals that have thepotential of damaging cells and tissues. These free radicals may includereactive oxygen species (ROS) such as superoxide, peroxynitrite andhydroxyl radicals, and potentially other reactive species that may betoxic to cells. For example, oxygen free radical induced lipidperoxidation is a well established pathogenetic mechanism in centralnervous system (CNS) injury such as that found in a number ofdegenerative diseases, and in ischemia (i.e., stroke). (Mitochondrialparticipation in the apoptotic cascade is believed to also be a keyevent in the pathogenesis of neuronal death.)

There are, moreover, at least two deleterious consequences of exposureto reactive free radicals arising from mitochondrial dysfunction thatadversely impact the mitochondria themselves. First, free radicalmediated damage may inactivate one or more of the myriad proteins of theETC. Second, free radical mediated damage may result in catastrophicmitochondrial collapse that has been termed “transition permeability.”According to generally accepted theories of mitochondrial function,proper ETC respiratory activity requires maintenance of anelectrochemical potential in the inner mitochondrial membrane by acoupled chemiosmotic mechanism. Free radical oxidative activity maydissipate this membrane potential, thereby preventing ATP biosynthesisand/or triggering mitochondrial events in the apoptotic cascade.

There is evidence that defects in oxidative phosphorylation within themitochondria are at least a partial cause of sporadic AD. The enzymecytochrome c oxidase (COX), which makes up part of the mitochondrialelectron transport chain (ETC), is present in normal amounts in ADpatients; however, the catalytic activity of this enzyme in AD patientsand in the brains of AD patients at autopsy has been found to beabnormally low. This suggests that the COX in AD patients is defective,leading to decreased catalytic activity that in some fashion causes orcontributes to the symptoms that are characteristic of AD.

One hallmark pathology of AD is the death of selected neuronalpopulations in discrete regions of the brain. Cell death in AD ispresumed to be apoptotic because signs of programmed cell death (PCD)are seen and indicators of active gliosis and necrosis are not found(Smale et al., Exp. Neurolog. 133: 225-230, 1995; Cotman et al., Molec.Neurobiol. 10: 19-45, 1995). The consequences of cell death in AD,neuronal and synaptic loss, are closely associated with the clinicaldiagnosis of AD and are highly correlated with the degree of dementia inAD (DeKosky et al., Ann. Neurology 2757-464, 1990).

Mitochondrial dysfunction is thought to be critical in the cascade ofevents leading to apoptosis in various cell types (Kroemer et al., FASEBJ 9: 1277-1287, 1995), and may be a cause of apoptotic cell death inneurons of the AD brain. Altered mitochondrial physiology may be amongthe earliest events in PCD (Zamzami et al., J. Exp. Med. 182: 367-77,1995; Zamzami et al., J. Exp. Med. 181: 1661-72, 1995) and elevatedreactive oxygen species (ROS) levels that result from such alteredmitochondrial function may initiate the apoptotic cascade (Ausserer etal., Mol. Cell. Biol. 14: 5032-42, 1994). In several cell types,including neurons, reduction in the mitochondrial membrane potential(δψm) precedes the nuclear DNA degradation that accompanies apoptosis.In cell-free systems, mitochondrial, but not nuclear, enriched fractionsare capable of inducing nuclear apoptosis (Newmeyer et al., Cell 70:353-64, 1994). Perturbation of mitochondrial respiratory activityleading to altered cellular metabolic states, such as elevatedintracellular ROS, may occur in mitochondria associated diseases and mayfurther induce pathogenetic events via apoptotic mechanisms.

Oxidatively-stressed mitochondria may release a pre-formed solublefactor that can induce chromosomal condensation, an event precedingapoptosis (Marchetti et al., Cancer Res. 56: 2033-38, 1996). Inaddition, members of the Bcl-2 family of anti-apoptosis gene productsare located within the outer mitochondrial membrane (Monaghan et al., J.Histochem. Cytochem. 40: 1819-25, 1992) and these proteins appear toprotect membranes from oxidative stress (Korsmeyer et al, Biochim.Biophys. Act. 1271: 63, 1995). Localization of Bcl-2 to this membraneappears to be indispensable for modulation of apoptosis (Nguyen et al.,J. Biol. Chem. 269: 16521-24, 1994). Thus, changes in mitochondrialphysiology may be important mediators of apoptosis. To the extent thatapoptotic cell death is a prominent feature of neuronal loss in AD,mitochondrial dysfunction may be critical to the progression of thisdisease and may also be a contributing factor in other mitochondriaassociated diseases.

Focal defects in energy metabolism in the mitochondria, withaccompanying increases in oxidative stress, may be associated with AD.It is well-established that energy metabolism is impaired in AD brain(Palmer et al., Brain Res. 645: 338-42, 1994; Pappolla et al., Am. J.Pathol. 140: 621-28, 1992; Jeandel et al., Gerontol. 35: 275, 1989;Balazs et al., Neurochem. Res. 19: 1131-37, 1994; Mecocci et al., Ann.Neurol. 36: 747-751, 1994; Gsell et al., J. Neurochem. 64: 1216-23,1995). For example, regionally specific deficits in energy metabolism inAD brains have been reported in a number of positron emission tomographystudies (Kuhl, et al., J. Cereb. Blood Flow Metab. 7: S406, 1987; Grady,et al., J. Clin. Exp. Neuropsychol. 10: 576-96, 1988; Haxby et al.,Arch. Neurol. 4: 753-60, 1990; Azari et al., J. Cereb. Blood Flow Metab.13: 438-47, 1993). Metabolic defects in the temporoparietal neocortex ofAD patients apparently presage cognitive decline by several years. Skinfibroblasts from AD patients display decreased glucose utilization andincreased oxidation of glucose, leading to the formation ofglycosylation end products (Yan et al., Proc. Nat. Acad. Sci. U.S.A. 91:7787-91, 1994). Cortical tissue from postmortem AD brain shows decreasedactivity of the mitochondrial enzymes pyruvate dehydrogenase (Sheu etal., Ann. Neurol. 17: 444-49, 1985) and α-ketoglutarate dehydrogenase(Mastrogiacomo et al., J. Neurochem. 6: 2007-2014, 1994), which are bothkey enzymes in energy metabolism. Functional magnetic resonancespectroscopy studies have shown increased levels of inorganic phosphaterelative to phosphocreatine in AD brain, suggesting an accumulation ofprecursors that arises from decreased ATP production by mitochondria(Pettegrew et al., Neurobiol. of Aging 15: 117-32, 1994; Pettigrew etal., Neurobiol. of Aging 16: 973-75, 1995). In addition, the levels ofpyruvate, but not of glucose or lactate, are reported to be increased inthe cerebrospinal fluid of AD patients, consistent with defects incerebral mitochondrial electron transport chain (ETC) activity (Pamettiet al., Neurosci. Lett 199: 231-33, 1995).

Signs of oxidative injury are prominent features of AD pathology and, asnoted above, reactive oxygen species (ROS) are critical mediators ofneuronal degeneration. Indeed, studies at autopsy show that markers ofprotein, DNA and lipid peroxidation are increased in AD brain (Palmer etal., Brain Res. 645: 338-42, 1994; Pappolla et al., Am. J. Pathol. 140:621-28, 1992; Jeandel et al., Gerontol. 35: 275-82, 1989; Balazs et al.,Arch. Neurol. 4: 864, 1994; Mecocci et al., Ann. Neurol. 36: 747-751,1994; Smith et al., Proc. Nat. Acad. Sci. U.S.A. 88: 10540-10543, 1991).In hippocampal tissue from AD but not from controls, carbonyl formationindicative of protein oxidation is increased in neuronal cytoplasm, andnuclei of neurons and glia (Smith et al., Nature 382: 120-21, 1996).Neurofibrillary tangles also appear to be prominent sites of proteinoxidation (Schweers et al., Proc. Nat. Acad. Sci. U.S.A. 92: 8463, 1995;Blass et al., Arch. Veurol. 4: 864, 1990). Under stressed andnon-stressed conditions incubation of cortical tissue from AD brainstaken at autopsy demonstrate increased free radical production relativeto non-AD controls. In addition, the activities of critical antioxidantenzymes, particularly catalase, are reduced in AD (Gsell et al., J.Neurochem. 64: 1216-23, 1995), suggesting that the AD brain isvulnerable to increased ROS production. Thus, oxidative stress maycontribute significantly to the pathology of mitochondria associateddiseases such as AD, where mitochondrial dysfunction and/or elevated ROSmay be present.

Increasing evidence points to the fundamental role of mitochondrialdysfunction in chronic neurodegenerative diseases (Beal, Biochim.Biophys. Acta 1366: 211-223, 1998), and recent studies implicatemitochondria for regulating the events that lead to necrotic andapoptotic cell death (Susin et al., Biochim. Biophys. Acta 1366:151-168, 1998). Stressed (by, e.g., free radicals, high intracellularcalcium, loss of ATP, among others) mitochondria may release pre-formedsoluble factors that can initiate apoptosis through an interaction withapoptosomes (Marchetti et al., Cancer Res. 56: 2033-38, 1996; Li et al.,Cell 91: 479-89, 1997). Release of preformed soluble factors by stressedmitochondria, like cytochrome c, may occur as a consequence of a numberof events. In any event, it is thought that the magnitude of stress(ROS, intracellular calcium levels, etc.) influences the changes inmitochondrial physiology that ultimately determine whether cell deathoccurs via a necrotic or apoptotic pathway. To the extent that apoptoticcell death is a prominent feature of degenerative diseases,mitochondrial dysfunction may be a critical factor in diseaseprogression.

In a preferred embodiment of the present invention, the therapeutic orprophylactic administration of antioxidant compounds, and/or thediagnostic use thereof, is enhanced by stimulation of the SPG and/or itsrelated neuroanatomical structures, by using electrical stimulation,odorant presentation, and/or other means for stimulating the SPG or formodulating permeability of the BBB.

EXAMPLE 8 Therapeutics (β-Amyloid Inhibitors)

U.S. Patent Application Publication 2002/0042420 to Briem et. al.,describes a method to prepare compounds which may be capable ofinterfering (preferably in an inhibitory capacity) in the process of theformation of Aβ or its release from cells, or of reducing the activityof Aβ by inhibiting it. Their description has the further objective ofpreparing compounds which can be used effectively for the prevention ortreatment of Alzheimer's disease.

U.S. Patent Application Publication 2002/0025955 to Han et al.,describes the potential use of lactams that inhibit the processing ofamyloid precursor protein and, more specifically, inhibit the productionof Aβ-peptide, thereby potentially acting to prevent the formation ofneurological deposits of amyloid protein.

U.S. Patent Application Publication 2002/0022621 to Chaturvedula et al.,describes a series of arylacetamidoalanyl derivatives ofbenzodiazepinones, which are inhibitors of β-amyloid peptide productionand may be useful in the treatment of Alzheimer's disease and otherconditions characterized by aberrant extract cellular deposition ofamyloid.

U.S. Patent Application Publication 2001/0020097 to Audia et al.,describes compounds which inhibit β-amyloid peptide release and/or itssynthesis, and, accordingly, may have utility in treating Alzheimer'sdisease both prophylactically and therapeutically. Introduction of thecompounds into the brain, for therapeutic purposes, or out of the brain,for diagnostic purposes, may require crossing the BBB.

U.S. Pat. No. 6,211,235 to Wu et al., describes compounds which inhibitp-amyloid peptide release and/or its synthesis, and, accordingly, mayhave utility in treating Alzheimer's disease. It also describespharmaceutical compositions comprising a compound which may inhibitβ-amyloid peptide release and/or its synthesis when introduced eitherdirectly or indirectly into the brain. Direct techniques usually involveplacement of a drug delivery catheter into the host's ventricular systemto bypass the blood-brain barrier. One such implantable delivery systemused for the transport of biological factors to specific anatomicalregions of the body is described in U.S. Pat. No. 5,011,472 to Aebischeret al. Indirect techniques, which are generally preferred, usuallyinvolve formulating the compositions to provide for drug latentiation bythe conversion of hydrophilic drugs into lipid-soluble drugs.Latentiation is generally achieved through blocking of the hydroxy,carbonyl, sulfate, and primary amine groups present on the drug torender the drug more lipid soluble and amenable to transportation acrossthe BBB. Alternatively, the delivery of hydrophilic drugs may beenhanced by intra-arterial infusion of hypertonic solutions which maytransiently open the BBB to some extent.

However, without using the techniques described herein, no generalmethod is known to controllably open the BBB for the efficient deliveryof large-molecular weight pharmaceutical compounds, or compounds withhigh plasma protein binding.

In a preferred embodiment of the present invention, the therapeutic orprophylactic administration of the compounds described in this example(Example 8), and/or the diagnostic use thereof, is enhanced bystimulation of the SPG and/or its related neuroanatomical structures, byusing electrical stimulation, odorant presentation, and/or other meansfor stimulating the SPG or for modulating permeability of the BBB.

EXAMPLE 9 Therapeutics (β-Amyloidpolymerization Inhibitors)

Bernd Bohrmann et al. reported (J Biol Chem, Vol. 274, Issue 23,15990-15995, Jun. 4, 1999) that certain plasma proteins, atphysiological concentrations, are potent inhibitors of β-amyloid peptidepolymerization. These proteins are also present in cerebrospinal fluid,but at low concentrations having little or no effect on P-amyloid.Thirteen proteins representing more than 90% of the protein content inplasma and cerebrospinal fluid were studied. Quantitatively, albumin wasthe most important protein, representing 60% of the total amyloidinhibitory activity, followed by α-1-antitrypsin and immunoglobulins Aand G. Albumin suppressed amyloid formation by binding to the oligomericor polymeric beta-amyloid, blocking a further addition of peptide.

The results of Bohrmann et al. suggest that several endogenous proteinsare negative regulators of amyloid formation. Plasma contains at least300 times more amyloid inhibitory activity than cerebrospinal fluid.These findings may provide one explanation as to why β-amyloid depositsare not found in peripheral tissues but are only found in the centralnervous system. Moreover, the data suggest that some drugs that displayan affinity for albumin may enhance P-amyloid formation and promote thedevelopment of AD.

Increased penetration of plasma proteins into the CNS may, on the otherhand, have an inhibitory effect on P-amyloid polymerization,consequently slowing, or reversing, AD progression.

In a preferred embodiment of the present invention, the permeability ofthe BBB is enhanced by stimulation of the SPG and/or its relatedneuroanatomical structures, by using electrical stimulation, odorantpresentation, and/or other means for stimulating the SPG or formodulating permeability of the BBB, in order to permit P-amyloidpolymerization inhibitors naturally occurring in the blood, particularlyalbumin, to pass from the blood into the CNS.

EXAMPLE 10 Therapeutics (Microglial Activation Modulators)

Acute and chronic brain injuries can activate resident microglia(resident macrophage-like cells found in the central nervous system) aswell as recruit peripheral immune cells to injured brain regions thatcan exacerbate neuronal damage. Inflammatory processes can induce celldeath by (a) the release of proteases and free radicals that inducelipid peroxidation, (b) direct cytotoxic effects or (c) the phagocytosisof sublethally-injured neurons. The attenuation of microglia andperipheral immune cell activation has been correlated with significantneuronal protection in pre-clinical studies of ischemia, traumatic braininjury, spinal cord injury and Alzheimer's disease. U.S. PatentApplication Publication 20020022650 to Posmantur et al. describesmethods of modulating or inhibiting microglia activation comprising theadministration of a compound capable of inhibiting 5-LOX, FLAβ,attenuating degradation of IκBa or inhibiting nuclear translocation ofthe NF-KB active complex for the treatment of various disordersassociated with excessive production of inflammatory mediators in thebrain, among which is Alzheimer's disease.

In a preferred embodiment of the present invention, the therapeutic orprophylactic administration of the compounds described in this example(Example 10), and/or the diagnostic use thereof, is enhanced bystimulation of the SPG and/or its related neuroanatomical structures, byusing electrical stimulation, odorant presentation, and/or other meansfor stimulating the SPG or for modulating permeability of the BBB.

EXAMPLE 11 Therapeutics (NSAID)

Studies support an inverse relationship between anti-inflammatorymedications used for treating patients with rheumatoid arthritis and anassociated low prevalence of Alzheimer's disease (Rich, J. B. et al.,Neurology 45: 51-55, 1995). Controlled studies of twin pairs havingAlzheimer's disease onset greater than 3 years apart provide additionalsupport that prior treatment with anti-inflammatory medications serves aprotective role in Alzheimer's disease (Breitner, J. C. S. et al.,Neurology 44: 227-232, 1994). Specifically, controlled double-blindedstudies have found that the anti-inflammatory agent “indomethacin”administered orally has a therapeutic benefit for mild to moderatelycognitively-impaired Alzheimer's disease patients, and treatment withindomethacin during early stages of the disease has a retarding effecton disease progression compared to the placebo treated control group.(Rogers, J. et al., Neurology 43: 1609-1612, 1993). Alzheimer's patientswith moderate cognitive impairment treated with indomethacin alsoexhibit a reduction in cognitive decline. However, patients treated withoral indomethacin developed drug related adverse effects that requiredtheir treatment to be discontinued and their removal from the study.

U.S. Patent Application Publication 2001/0027309 to Elsberry describes amethod for treating Alzheimer's disease, comprising deliveringindomethacin or nonsteroidal anti-inflammatory drugs (NSAIDs) havingcyclooxygenase inhibitor action directly to the hippocampus or thelateral ventricle through an implanted catheter.

It may also be advantageous to allow NSAID and other anti-inflammatorydrugs into the CNS in combination with immunological (vaccine) treatmentof AD. A vaccine, made by Elan Corporation (Dublin, Ireland) and knownby its code name AN-1792, was tested in a clinical trial. In the trial,twelve volunteers were reported to have fallen seriously ill with braininflammation, forcing the vaccine's manufacturer to halt the trial andraising doubts about the product's clinical potential. The AN-1792vaccine had generated unusually intense enthusiasm among scientists andpatient advocates during the past two years, as experiments in micesuggested it could halt the progression of Alzheimer's and perhaps evencure the deadly disease.

In general, NSAIDs are known to be very extensively protein bound(>99%). This characteristic makes the penetration of NSAID into the CNSvery scarce, since they are usually bound to plasma proteins havingmolecular weights of around 70 kDa.

Therefore, allowing macromolecules into the CNS is expected to allow theintroduction of anti-inflammatory drugs. These, on their own, or inconjunction with immunological or other therapeutic approaches, canserve as an effective treatment for AD.

In a preferred embodiment of the present invention, the therapeutic orprophylactic administration of NSAIDs and other anti-inflammatoryagents, and/or the diagnostic use thereof, is enhanced by stimulation ofthe SPG and/or its related neuroanatomical structures, by usingelectrical stimulation, odorant presentation, and/or other means forstimulating the SPG or for modulating permeability of the BBB.

In another preferred embodiment of the present invention, theadministration of a vaccine is enhanced by stimulation of the SPG and/orits related neuroanatomical structures, by using electrical stimulation,odorant presentation, and/or other means for stimulating the SPG or formodulating permeability of the BBB.

EXAMPLE 12 Therapeutics (Vaccine)

U.S. Patent Application Publication 2002/0009445 to Du et al., discussesthe use of an anti-Aβ antibody for diagnosing and/or treating amyloidassociated diseases, especially Alzheimer's disease. They indicate thatnaturally-occurring Aβ antibodies exist in biologically relevant fluids,i.e., CSF and plasma, and that levels of these antibodies differ betweennormal age-matched healthy controls and AD patients. Based on thesefindings it was concluded and then supported by experiments that theseantibodies can be used for diagnosis and treatment of amyloid associateddiseases and especially of Alzheimer's disease. In the context of thisapplication, the terms “anti-Aβ antibodies” and “Aβ antibodies” are usedinterchangeably to designate the antibody of their invention. Anembodiment of their diagnostic method uses lumbar CSF samples, on whichAβ antibody levels were determined utilizing an ELISA assay in which theAβ peptide was used as the capture ligand.

In a preferred embodiment of the present invention, the therapeutic orprophylactic administration of anti-Aβ antibodies, and/or the diagnosticuse thereof, is enhanced by stimulation of the SPG and/or its relatedneuroanatomical structures, by using electrical stimulation, odorantpresentation, and/or other means for stimulating the SPG or formodulating permeability of the BBB.

EXAMPLE 13 Therapeutics (Other Approaches)

U.S. Patent Application Publication 2002/0022593 to Yue describes amethod of treating neurodegenerative dysfunctions and aging symptoms byadministering a therapeutically-effective amount of relaxin (apolypeptide hormone, whose molecular weight is between 5,700 to 6,500Da) to a patient. Neurodegenerative dysfunctions potentially amenable totreatment with relaxin include Alzheimer's, attention deficit disorder,Parkinson's, and others. The aforementioned method is based on therecognition that some of the symptoms associated with aging and/orneurodegenerative dysfunctions can be alleviated by relaxin, and may infact be caused by a decrease of relaxin in the bloodstream. This lack ofrelaxin in the blood stream may be congenital or the result of anothermechanism which suppresses the normal production or action of relaxin.

In a preferred embodiment of the present invention, the therapeutic orprophylactic administration of relaxin, and/or the diagnostic usethereof, is enhanced by stimulation of the SPG and/or its relatedneuroanatomical structures, by using electrical stimulation, odorantpresentation, and/or other means for stimulating the SPG or formodulating permeability of the BBB.

U.S. Patent Application Publication 2002/0019412 to Andersen et al.,describes novel inhibitors of Protein Tyrosine Phosphatases (PTPase's)such as PTPIB, CD45, SHP-1, SHP-2, PTPa, LAR and HePTP or the like, fortreatment of various systemic and CNS-related disorders, includingAlzheimer's disease.

In a preferred embodiment of the present invention, the therapeutic orprophylactic administration of PTPase's, and/or the diagnostic usethereof, is enhanced by stimulation of the SPG and/or its relatedneuroanatomical structures, by using electrical stimulation, odorantpresentation, and/or other means for stimulating the SPG or formodulating permeability of the BBB.

U.S. Patent Application Publication 2002/0006959 to Henderson describesa method of potentially treating or preventing dementia of Alzheimer'stype, or other loss of cognitive function caused by reduced neuronalmetabolism, comprising administering an effective amount of medium chaintriglycerides to a patient in need thereof.

In a preferred embodiment of the present invention, the therapeutic orprophylactic administration of medium chain triglycerides, and/or thediagnostic use thereof, is enhanced by stimulation of the SPG and/or itsrelated neuroanatomical structures, by using electrical stimulation,odorant presentation, and/or other means for stimulating the SPG or formodulating permeability of the BBB.

EXAMPLE 14 Diagnostics

Accurate diagnosis of AD during life is highly desirable. However,clinical evaluation is at best only about 80% accurate. Therefore, thereexists a need to identify specific biochemical markers of AD. So far,analysis of blood or cerebrospinal fluid (CSF) has not yielded abiochemical marker of sufficient diagnostic value (Blass et al., 1998),although detectable differences are reported in the levels of certainproteins (Motter et al., Ann. Neurol. 38, 643-648, 1995).

Although recent reports of using positron-emission tomography (PET)(Reiman, E. M., et al., New Eng. J. Med., 334: 752-758, 1996),determining the genotype of an individual's ApoE, or measuring thelevels of β-amyloid protein in cerebral spinal fluid may be promising,diagnosis of AD is currently confirmed only upon autopsy to determinethe presence of P-amyloid senile plaques.

Moreover, recent studies have shown that damage to CNS neurons due toAlzheimer's disease begins years before clinical symptoms are evident(Reiman, E. M. et al., New Eng. J. Med., 334: 752-758, 1996), suggestingthat therapy could begin in the pre-symptomatic phase of the disease ifa sensitive diagnostic test and targeted therapies were available. Thereexists a great need to determine the physiological mechanisms involvedwith the disease and for an accurate and easy to perform assay toevaluate the risk of developing Alzheimer's disease.

U.S. Patent Application Publication 2002/0042121 to Riesner et al.,describes a method for the diagnostic detection of diseases associatedwith protein depositions (pathological protein depositions) by measuringan association of substructures of the pathological protein depositions,structures forming pathological protein depositions, structurescorresponding to pathological protein depositions and/or pathologicalprotein depositions as a probe or a target.

U.S. Patent Application Publication 2002/0028462 to Tanzi et al.,describes a diagnostic method for AD based on genotyping theAlpha-2-Macroglobulin locus. A statistically-significant correlation wasfound between inheritance of particular alleles of theAlpha-2-Macroglobulin gene and the occurrence of AD. The diagnosticmethod involves the isolation of nucleic acid from an individual andsubsequent genotyping by means such as sequencing or restrictionfragment length polymorphism analysis. The invention also describes ameans for genotype analysis through protein isotypingAlpha-2-Macroglobulin variant proteins. Finally, kits for nucleic acidanalysis or protein analysis are described.

U.S. Patent Application Publication 2002/0022242 to Small et al.,describes a method for the diagnosis of AD in a patient by detecting thepresence of BuChE with an altered glycosylation pattern in anappropriate body fluid sample. It has been established that on averageapproximately 93.6% of the BuChE in the CSF of AD patients binds toConcanavalin (Con A). All embodiments of this method are described asusing either CSF or brain tissue as the sample, thereby adding a riskfactor to the diagnostic procedure.

U.S. Patent Application Publication 2002/0019519 to Bingham et al.,describes the use of KIAA0551 polypeptides and polynucleotides in thedesign of protocols for the treatment of and also for diagnostics assaysof AD.

U.S. Patent Application Publication 2001/0044126 to Holtzman et al.,describes a diagnostic method for identifying individuals at risk fordeveloping Alzheimer's disease, which relies on elevated levels of theratio of Aβ₄₀/Aβ₄₂ associated with lipoproteins in the cerebrospinalfluid of individuals at risk as compared to this ratio in the overallpopulation. It is based on the assessment that the lipoprotein fractionof CSF in such individuals has such increased ratios.

U.S. Patent Application Publication 2002/0019016 to Vanmechelen et al.,describes a method for the differential diagnosis of an individualsuffering from AD versus an individual suffering from anotherneurological disease (dementia with Lewy bodies, Parkinson's diseasewithout dementia, multi-system atrophy and/or progressive supranuclearpalsy), where phospho-tau is used as a neurological marker, the level ofwhich is measured in a CSF sample.

U.S. Patent Application Publication 2002/0009445 to Du et al., cited andsummarized hereinabove, describes the use of an anti-Aβ antibody fordiagnosing and/or treating amyloid associated diseases, especiallyAlzheimer's disease.

U.S. Patent Application Publication 2002/0006627 to Reitz et al.,describes a method for diagnosing Alzheimer's disease involving analysisof a test sample in such a way that β-amyloid_(1-42 or Aβ)3pE iscompletely or nearly completely (i.e., thoroughly) dissociated frombinding proteins prior to the analysis of the levels of β-amyloid₁₋₄₂ orAβ3pE.

U.S. Patent Application Publication 2002/0002270 to Zinkowski et al.,describes a preparation comprising Alzheimer's disease antigen (A68), aswell as methods of obtaining this purified antigen (Ag), and methodsusing the purified Ag, for instance, for diagnosing Alzheimer's Disease,and also describes treatments of these Ags that enhance their reactivitywith autoantibodies directed against A68. These treatments includetreatment with hypericin, free fatty acids, and/or hydroxynonenal orother advanced glycation end products.

U.S. Patent Application Publication 2001/0026916 to Ginsberg et al.,describes a method of identifying senile plaques, neurofibrillarytangles and neuropil threads in brain tissue which comprises contactingbrain tissue with a fluorescent dye capable of intercalating selectivelyinto nucleic acids and detecting any fluorescence in the brain tissueindicative of senile plaques, neurofibrillary tangles and neuropilthreads in the brain tissue.

U.S. Pat. No. 6,238,892 to Mercken et al., describes the use of amonoclonal antibody which forms an immunological complex with aphosphorylated epitope of an antigen belonging to human abnormallyphosphorylated tau protein. The tau protein can be obtained from a brainhomogenate, itself isolated from the cerebral cortex of a patient havingAlzheimer's disease. Methods for in-vivo diagnosis of AD using thelatter mAb, should preferably employ techniques that leaves the meningesintact. Such methods are described in this patent as being yetundeveloped.

The '892 patent provides an overview of tau (complete references havebeen provided):

Tau is a microtubule-associated protein which is synthesized in theneurons (Kosik, K. S. et al., Ann. Neurol. 26, 352-361, 1989) of severalspecies, including humans, and which is abundantly present in the axonalcompartment of these neurons (Binder, L. I. et al., J Cell Biol., 101:1371-1378, 1985). Functionally the tau protein is involved in thepolymerization of tubulin (Weingarten, M. D. et al., Proc. Natl. Acad.Sci. U.S.A. 72, 1868-1862, 1975) and presumably in reducing microtubuleinstability (Bre, M. H. et al., Cell Motil. Cytoskeleton 15, 88-98,1990).

Tau protein is also the major constituent of paired helical filaments(PHF), characteristic structures found as neurofibrillary tangles intissue sections of the brain of Alzheimer patients (Greenberg, S. etal., Proc. Natl. Acad. Sci. U.S.A., 87, 5827-5831, 1990; Lee, V. M.-Y.et al., Science, 251, 675-678, 1991). The protein exists as a family ofdifferent isoforms of which 4 to 6 isoforms are found in normal adultbrain but only 1 isoform is detected in fetal brain (Goedert, M. et al.,Neuron 3, 519-526, 1989). The diversity of the isoforms is generatedfrom a single gene by alternative mRNA splicing (Himmler, A., Mol. Cell.Biol., 9, 1389-1396, 1989). The most striking feature of tau protein aspredicted from molecular cloning is a stretch of 31 or 32 amino acidsoccurring in the carboxy-terminal part of the molecule that is repeated3 or 4 times. Additional diversity is generated through 29 or 58 aminoacid long insertions in the NH2-terminal part of the molecules (Goedert,M. et al., Neuron 3, 519-526, 1989).

Tau variants of 64 and 69 kDa, which are abnormally phosphorylated asrevealed by the decrease in their molecular mass observed after alkalinephosphatase treatment, have been detected exclusively in brain areasshowing neurofibrillary tangles and senile plaques (Flament, S. et al.,A., J. Neurol. Sci. 92, 133-141, 1989; Flament, S. et al., Brain Res.516, 15-19, 1990; and Flament, S. et al., Nature 346, 6279, 1990). Thesites of phosphorylation by 4 different kinases have been mapped in theC-terminal microtubule-binding half of tau and it could be shown thatthe action of a calcium calmodulin-dependent kinase on bacteriallyexpressed tau resulted in a phosphorylation of Ser(405) which induced alower electrophoretical mobility (Steiner, B. et al., The EMBO Journal9, 3539-3544, 1990).

Several antibodies are reported that show reactivity to human tau eitherbecause they are directed to nonspecific phosphorylated epitopes presenton neurofilament and subsequently shown to cross-react with normal andabnormally phosphorylated tau (Nukina, N. et al., Proc. Natl. Acad. Sci.U.S.A. 84, 3415-3419, 1987; Ksiezak-Reding et al., Proc. Natl. Acad.Sci. U.S.A., 84, 3410-3414, 1987) or because they recognized specificepitopes on normal and abnormally phosphorylated tau.

The Alz50 monoclonal antibody (Wolozin, B. L. et al., Science 232,648-650, 1986; Nukina et al., Neurosci. Lett 87, 240-246, 1988)recognizing a phosphate-independent epitope present on tau variants ofbovine origin and of normal and abnormally phosphorylated tau from humanorigin (Ksiezak-Reding, H. et al., J. Biol. Chem., 263, 7943-7947, 1988,Flament, S. et al., Brain Res. 516, 15-19, 1990; and Flament, S. et al.,Nature 346, 6279, 1990) belongs to the latter class of antibodies. Theepitope recognized by this monoclonal is specifically expressed in thesomatodendritic domain of degenerating cortical neurons during Alzheimerdisease (Delacourte, A. et al., Acta Neuropathol. 80, 111-117, 1990).

The Alz50 epitope has recently been mapped to the NH2-terminal part ofthe tau molecule (Ksiezak-Reding, H. et al., J. Neurosci. Res., 25,412-419, 1990; Goedert, M. et al., Neurosci. Lett., 126, 149-154, 1991).Due to its cross-reactivity with normal tau, this antibody is only ableto discriminate normal from abnormally phosphorylated tau by the use ofWestern blotting detection of brain homogenates or by ammoniumsulfate-concentrated CSF, or also by using a sandwich immunoassay onbrain homogenates (Ghanbari et al., J. Clin. Laboratory Anal. 4,189-192, 1990; Wolozin, B. et al, Ann. Neurol. 22, 521-526, 1987;European Patent Application Publication EP 0 444 856 to Ghanbari etal.). A CSF-based assay using antibodies directed against PHF was firstdescribed by Mehta et al., The Lancet, Jul. 35, 1985, but showsconsiderable overlap between Alzheimer CSF and CSF from controls. Theepitope recognized by this antibody was identified as part of ubiquitin(Perry et al., J. Neurochem. 52, 1523-1528, 1989).

Other monoclonal antibodies have been developed to recognize tauprotein. For instance, monoclonal antibody 5E2 was raised byimmunization with human fetal heat-stable microtubule-associatedproteins and recognizes an epitope spanning amino acids 156-175 which ispresent in normal and abnormally phosphorylated tau (Kosik, K. S. etal., Neuron., 1, 817-825, 1988).

Other antibodies such as tau 1 and several others were raised byimmunization with bovine tau, bovine heat-stable microtubule-associatedprotein, or rat brain extracts (Binder, L. I. et al., J. Cell Biol. 101,1371-1378, 1985; Kosik, K. S. et al., Neuron., 1, 817-825, 1988), andmost of the antibodies recognize the normal and the abnormallyphosphorylated tau (Ksiezak-Reding, H. et al., J. Neurosci. Res., 25,412-419, 1990).

An antibody named “423”, raised against the core of PHF, reactedspecifically with a 9.5 and 12-kDa fragment of the tau protein,localized in the repetitive elements of tau, but recognized neithernormal human tau nor the abnormally phosphorylated tau in Alzheimer'sbrain (Wischik, C. H. et al., Proc. Natl. Acad. Sci. U.S.A., 85,4884-4888, 1988). This antibody has been used to discriminate AlzheimerPHF pathology from normal controls in brain homogenates (Harrington, C.R. et al., J. Immunol. Methods 134, 261-271, 1990; PCT PublicationWO89/03993 to Wischik et al.).

Thus far, none of all the antibodies described heretofore has had anabsolute specificity for the abnormally phosphorylated tau either byimmunohistology, Western blotting, or ELISA. Quantitative measurementsof normal and abnormally phosphorylated tau have until now only beenable to detect tau in brain homogenates, in brain extracts containingPHF, or in concentrated CSF samples after Western blotting (Ghanbari H.A. et al., J. Clin. Laboratory Anal. 4, 189-192, 1990; Harrington C. R.et al., J. Immunol. Methods 134, 261-271, 1990, Wisniewski, H. M. etal., Biological Markers of Alzheimer's Disease, Boller, Katzman, Rascol,Signoret & Christian eds., 23-29, 1989; Wolozin, B. et al., Ann. Neurol.22, 521-526, 1987).

U.S. Patent Application Publication 2001/0018191 to Mercken et al.,describes monoclonal antibodies which are described as specifically ableto detect only abnormally-phosphorylated tau present in brain tissuesections, in brain extracts, or in body fluids such as cerebrospinalfluid. It is required that a method for bypassing the BBB be employed inorder to introduce the monoclonal antibodies into the CNS.

U.S. Patent Application Publication 2001/0014670 to Balin et al.,describes a method of treating Alzheimer's disease in a mammalcomprising administering to the mammal an anti-microbial agent havinganti-Chlamydia pneumoniae activity. The description also relates to amethod of diagnosing Alzheimer's disease in a mammal comprisingmeasuring the serum anti-Chlamydia pneumoniae antibody titer in apatient suspected of having Alzheimer's disease. It is required that amethod for bypassing the BBB be employed in order to communicate thetherapeutic compounds, antibodies, into the CNS, or to be able toevaluate presence of diagnostic agents (e.g. C. Pneumoniae) in aminimally invasive method.

U.S. Pat. No. 6,287,793 to Schenk et al., describes methods for theidentification of key diagnostic antibodies, antigens, diagnostic kitsand methods for diagnosis for AD, where the diagnostic procedure uses abiological fluid from a subject—most preferred are plasma and CSFsample.

Inducing changes in BBB permeability, as provided by preferredembodiments of the present invention, is useful for detectingacetylcholinesterase in human patients. Loss of acetylcholinesterase inhumans is associated with brain disorders, such as dementia andepilepsy, muscle disorders, and disorders of the digestive system. Themethods of some embodiments of the present invention are particularlyuseful for detecting acetylcholinesterase in the brain of a patientsuspected of suffering from a dementia, such as Alzheimer's disease,thereby allowing the diagnosis, estimating the severity of, andmonitoring the progression of the dementia. Certain brain disorders anddementia, including Alzheimer's disease, are known to be accompanied bya decrease in acetylcholinesterase concentration in the brain. Thus,monitoring the concentration of acetylcholinesterase in the brain of apatient suspected of suffering from a brain disorder or dementiatypically allows diagnosis of the disorder or dementia, monitoring itsprogression, and/or estimating its severity. Advantageously, thisdiagnosis and monitoring is simply performed, for example, bystimulating the SPG using techniques described herein, and,simultaneously or shortly thereafter, extracting a blood sample usingstandard lab techniques. Since the increase in BBB permeability allowsthe acetylcholinesterase to pass therethrough, it is quickly in thesystemic bloodstream and detectable in the blood sample. It is to beunderstood that other compounds of diagnostic value can be extractedusing essentially the same technique.

The methods of some embodiments of the present invention can be used toprovide a brain image that shows the distribution and relativeconcentrations of acetylcholinesterase (or other compounds of diagnosticvalue) in a patient's brain, thereby allowing diagnosis, estimating theseverity of, and analysis of the progression of a disorder or dementiain a patient. The methods of some embodiments of the invention cantherefore be used to diagnosis, estimate the severity, and monitor theprogression of any dementia, known or to be discovered, that isaccompanied by a detectable change in concentration ofacetylcholinesterase or other compounds of diagnostic value in thebrain. In a preferred embodiment, a molecule such as an antibody whichis attracted to acetylcholinesterase is injected, swallowed, orotherwise introduced systemically, and its passage into the CNS isfacilitated by techniques described herein for increasing permeabilityof the BBB. Imaging techniques which are able to detect the introducedmolecule are then utilized to determine the locations or quantities ofacetylcholinesterase or other diagnostic compounds to which the moleculeis attached.

Some of the diagnostic techniques mentioned above indicate to theinventors that there is a need for performing diagnostic tests oncertain bio-chemical characteristics of the CSF by using a simple bloodtest. Other diagnostic techniques mentioned above indicate to theinventors that there is a need for increasing the permeability of theBBB using techniques described herein in order to facilitate the passageof diagnostic molecules into the CNS, where the molecules can bedetected, such as by imaging. Diagnostic procedures, which are on onehand highly accurate and on the other minimally invasive, typicallysubstantially improve the management of AD, when applied in accordancewith a preferred embodiment of the present invention. In a preferredembodiment of the present invention, the diagnostic techniques describedin this example (Example 14) are enhanced and/or enabled by stimulationof the SPG and/or its related neuroanatomical structures, by usingelectrical stimulation, odorant presentation, and/or other means forstimulating the SPG or for modulating permeability of the BBB.

The stimulation techniques described herein may facilitate the diagnosisof a number of CNS conditions, including, but not limited to, thefollowing conditions:

-   -   neurodegenerative conditions, such as Alzheimer's disease,        Parkinson's Disease, ALS, age-associated cognitive decline,        progressive supranuclear palsy, vascular (i.e., multi-infarct)        dementia, Lewy body dementia, Huntington's Disease, Down's        syndrome, normal pressure hydrocephalus, corticobasal ganglionic        degeneration, multisystem atrophy, head trauma, Creutzfeld-Jacob        disease, viral encephalitis and hypothyroidism, a degenerative        disorder associated with learning, memory or cognitive        dysfunction, cerebral senility, multi-infarct dementia and        senile dementia, and electric shock induced amnesia or amnesia;    -   neoplastic processes (either primary or metastatic), such as        neuroectodermal tumors, malignant astrocytomas, and        glioblastomas;    -   immune- and autoimmune-related disorders, such as HIV and        multiple sclerosis; and    -   CNS inflammatory processes.

The stimulation techniques described herein may facilitate the imagingof various aspects of the CNS, including biochemical aspects (e.g., GGMin late onset Tay-Sachs disease, dopamine in Parkinson's Disease),morphological aspects (e.g., ventricular dimensions in hydrocephalus),and functional aspects (e.g., glucose utilization in brain tumors).

In an embodiment of the present invention, stimulation of an MTS isconfigured to increase the transport of a diagnostic agent across theBBB from a non-CNS tissue, such as the systemic blood circulation, intothe CNS. The diagnostic agent is typically administered to the systemicblood circulation, such as intravenously, and a diagnostic procedure,typically an imaging modality, is then performed directly on the CNS.For some applications, the diagnostic agent comprises a tracer agent,such as an imaging contrast agent, for example, a Magnetic ResonanceImaging (MRI) contrast agent, a Single Photon Emission ComputedTomography (SPECT) radioisotope, a Positron Emission Tomography (PET)radioisotope, an ultrasound contrast enhancer, or an X-ray contrastagent (e.g., for a Computerized Tomography (CT) or angiography imagingsequence).

In an embodiment, the tracer is configured to be disease-specific,typically by conjugation to a biochemical agent for enhancing certainproperties or constituents of the CNS (or another physiologicalcompartment). The conjugation is performed either before administrationof the agent to the patient, or the conjugation occurs within thesystemic circulation, the CNS, or another physiological compartment.Examples of such constituents include selected proteins, cells,biotoxins, pathological tissue, or other biochemical entities that mayaid in diagnosis of a CNS condition, such as, for example, the HER2protein that is overexpressed on the outer membrane of malignant tumors,or certain interleukins, the receptors of which are abundant on thesurface membranes of certain types of cancerous cells. In theseapplications, the tracer may comprise a disease-specific (endogenous orexogenous) biochemical entity, or may comprise a biochemical entity thatrelates to a broad group of pathological states (e.g., a probe forinflammatory markers).

For some applications, such diagnostic agents are conjugated to thefollowing types of biochemical agents:

-   -   Antibodies to proteins which are indicative of neoplastic        processes, such as beta-Amyloid monoclonal antibody (mAb) or        polyclonal antibody (pAb), and anti-HER2 mAb; and/or    -   Interleukins (cytokines whose amino acid structure is known),        such as IL-1-IL18, TNF, IL-1 beta, IL-1ra, and TNF beta. This        groups of macromolecules consists of both pro-inflammatory        (e.g., IL-6, IL-8) and anti-inflammatory (e.g., IL-4, IL-10)        proteins that affect the growth, proliferation, differentiation,        regeneration, and secretion of various immuno-active cells        (e.g., B, T, CD4+ cells) and also the processes of hematopoiesis        and lymphopoiesis. Some of these macromolecules are also        produced by immune cells, such as B cells, T cells, macrophages,        and acute-phase response proteins. Some of these cytokines are        overexpressed by malignant cell lines, as well as in cases of        inflammation (e.g., adult T cell leukemia cell lines and        Epstein-Barr virus transformed B cells). Such cytokines        therefore generally represent diagnostic targets for neoplastic        processes.

In an embodiment of the present invention, stimulation of an MTS isconfigured to increase the transport of a biochemical agent across theBBB from the CNS to a non-CNS tissue, such as the systemic bloodcirculation. Such biochemical agents are typically disease-specificbiochemical markers. Prior to stimulation of an MTS to increase BBBpermeability, the concentration of such a biochemical agent is typicallygreater in the CNS than in the systemic circulation, i.e., there is aconcentration gradient across the endothelium. Therefore, increasing thepermeability of the BBB, typically acutely, generally releases the agentinto the systemic circulation. Once in the systemic circulation,diagnosis is typically performed by sampling a body tissue or fluid,typically blood, and analyzing the whole blood, plasma, or serum.Analysis is typically performed using a biochemical assay or anotheranalytical procedure, such as imaging, in order to qualitatively orquantitatively probe the presence of the biochemical agent of interest,a metabolite thereof, or a chemical or biological derivative thereof.

Diagnostic assay modalities typically applicable to the techniquesdescribed herein include, but are not limited to, High Purity LiquidChromatography (HPLC), SMAC, Enzyme Linked Immuno-Sorbent Assay (ELISA),electrophoresis, gel filtration, UV spectrophotometry,HPLC/fluorescence, Fluorescence Polarization Immunoassay (FPIA),HPLC/UV, Gas Chromatography/GC/EC, capillary electrophoresis, mobilityshift combination assay, bioluminescent assay, flow immunoassay,Polymerase Chain Reaction (PCR) ELISA, gamma counter, beta counter,chemiluminescence immunoassay (e.g., chemiluminescent ELISA),Dissociated Enhanced Lanthanide Fluorescence Immunoassay (DELFIA),Enzyme Immunoassay (EIA), Fluorescence Immunoassay (FIA),Immunoradiometric Assay (IRMA), Radioimmunoassay (RIA), andScintillation Proximity Assay (SPA).

Imaging modalities typically applicable to the techniques describedherein include, but are not limited to, PET, SPECT, CT, MRI, magneticresonance spectroscopy (MRS), Functional Magnetic Resonance Imaging(fMRI), Proton MRSI, Single-voxel proton MRS, Multi-nuclear MRS, gammacamera, and beta camera.

For some applications, techniques for transporting diagnostic agentsfrom the systemic circulation to the CNS are used to transport one ormore of the following radioisotopes for facilitating nuclear imagingmodalities, such as PET, SPECT, and gamma cameras: 7Be, 22Na, 46Sc, 48V,51Cr, 54Mn, 56Co, 65Zn, 75Se, 83Rb, 85Sr, 88Zr, 95 mTc, 103Ru, and 99Rh.These techniques may also be used for transporting one or more of thefollowing diagnostic agents for facilitating PET: 18F-FDG, 18F-FUdR,11C-MET, 11C-TYR, 15C-O2, 15C-O, H215O, 82Rb, 11C-5-HTP, 11C-L-DOPA,11C-L-DEP, U-5-HIAA, 99 mTc, 201T1, 111In-Oncoscint, and 1502. Thesetechniques may also be used for transporting one or more of thefollowing diagnostic agents for facilitating SPECT: I-123 ligands (e.g.,I-123-IMP, Iodine-123-QNB, Iodine-123-Iodine labeled ligands IBZM andIBZP), Tc-99m ligands (e.g., Tc-99m-hexamethyl propylamine oxime,Tc-Technetium-99m-bicisate), and Xenon-133 ligands.

The techniques described herein may also be used to transport thediagnostic agents and types of diagnostic agents shown in the followingtable. Although the agents are categorized by typical diagnostic aimsfor which they are generally appropriate, the techniques describedherein are not limited to facilitating transport for these diagnosticaims. Cell proliferation ¹¹C-TdR, ¹⁸F-3′FLT, ¹²⁴I-IUdR, ⁷⁶Br- FbrAUAngiogenesis Blood flow ¹⁵O-water, ^(99m)Tc-sestamibi, ²⁰¹Tl- thallium,¹³³Xe-saline Blood volume ¹⁵O— or ¹¹C-carbon monoxide-labeled Capillarypermeability erythrocytes (RBCs), ^(99m)Tc-RBCs ⁸²Rb, ⁶⁸Ga-DTPA,⁶⁸Ga-transferrin, ¹⁸F—, ¹²³I—, ¹³¹I—, ¹²⁴I— or ^(99m)Tc-labeled albuminOxygen metabolism ¹⁵O (oxygen) Hypoxia ¹⁸F-fluoromisonidazole, ⁶¹Cu— or⁶⁴Cu- ATSM, ¹⁸F-EF1, ¹⁸F-EF5 Transporter up-regulation Amino acidtransporters ¹¹C-methionine, ¹⁸F-FET, ¹⁸F-FACBC Nucleoside transporters¹¹C-FMAU Choline transporter ¹⁸F-fluorocholine Glucose transporter¹¹C-3OMG, ¹⁸F-FDG Cell surface receptors/ antigens (endothelial cellsand tumor cells) Transferrin receptors ⁶⁷Ga-transferrin, ¹¹¹In-DTPAtransferrin EGF receptor (radiolabeled chelate antibody or peptide)Benzodiazepine receptor iodinated-PK11195 Other cell surface receptors/antigens (e.g., Flt1 and Flk1/ KDR receptors for VEGF) Cell matrixantigens Integrins (RGD- and other radiolabeled peptides)

For some applications, techniques for transporting diagnostic agentsfrom the systemic circulation to the CNS are used to transport one ormore of the following contrast agents for facilitating MRI: gadoliniumchelates (e.g., Gd-DTPA, Gd-DOTAβ, Gd-EOB-DTPA), manganese chelates,paramagnetic iron oxide particles (e.g., polydisperse iron oxideparticles, with a partial dextran coat, or ultrasmall superparamagneticiron oxide-USPIO), and hyperpolarized gases (e.g., ³He¹²⁹Xe).

For some applications, techniques for transporting diagnostic agentsfrom the systemic circulation to the CNS are used to transport one ormore of the following contrast agents for facilitating ultrasoundimaging: polymer microbubbles, microscopic bubbles (e.g., Imavist™),investigational agent PB127-filled (polylactide/albumin) ornitrogen-filled microspheres, and iron oxide particles calledferumoxtran.

For some applications, techniques for transporting diagnostic agentsfrom the systemic circulation to the CNS are used to transport one ormore of the following contrast agents for facilitating CT: radiopaquetracers (e.g., dysprosium-, iodine- and gadolinium-based contrastagents) and stable xenon gas.

For some applications, techniques for transporting diagnostic agentsfrom the systemic circulation to the CNS are used to transportdiagnostic agents for facilitating optical intrinsic signal (OIS)imaging.

For some applications, the stimulation techniques described herein areused to facilitate diagnosis of Alzheimer's disease or other conditionsof the CNS in conjunction with techniques described in the followingpatents. It should be appreciated by those of skill in the art that thefollowing techniques are set forth for demonstrative purposes. However,those of skill in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentsdisclosed and still obtain a like or similar result without departingfrom the spirit and scope of the invention.

U.S. Pat. No. 4,666,829 to Glenner et al., which is incorporated hereinby reference, describes a polypeptide and fragments thereof that may beused to produce antibodies useful in a diagnostic test for Alzheimer'sdisease. Nucleotide probes corresponding to portions of the polypeptideare also described as useful for diagnostic purposes. In an embodimentof the present invention, stimulation techniques described herein forfacilitating transport of diagnostic agents from the systemic bloodcirculation to the CNS are used in conjunction with techniques describedin the '829 patent.

U.S. Pat. No. 4,874,694 to Gandy et al., which is incorporated herein byreference, describes a diagnostic method for neurological andpsychiatric disorders, utilizing the cerebrospinal fluid incubated inthe presence of 32-P labeled ATP and an appropriate protein kinase.After termination of the reaction, a sample is applied to gels forelectrophoresis. Subsequent autoradiography results in adisease-specific protein pattern that can be used for diagnosis ofdisorders such as Alzheimer disease, Huntington disease, Parkinsondisease, dystonia ataxia, schizophrenia, epilepsy brain tumors, brainirradiation, head trauma, and acute and chronic encephalitic andvascular disease. In an embodiment of the present invention, stimulationtechniques described herein for facilitating transport of biochemicalagents from the CNS to the systemic blood circulation are used inconjunction with techniques described in the '694 patent.

U.S. Pat. No. 6,358,681 to Ginsberg et al., which is incorporated hereinby reference, describes methods for detecting RNA in brain tissue inorder to diagnose Alzheimer's disease. In an embodiment of the presentinvention, stimulation techniques described herein for facilitatingtransport of biochemical agents from the CNS to the systemic bloodcirculation are used in conjunction with techniques described in the'681 patent.

U.S. Pat. No. 6,329,531 to Turner et al., which is incorporated hereinby reference, describes the use of optical diagnostic agents in in vivoand in vitro diagnosis of neurodegenerative diseases such as Alzheimer'sdisease by means of near infra-red radiation (NIR radiation) as acontrasting agent in fluoresecence and transillumination diagnosis inthe NIR range. Diagnostic agents containing such components are alsodescribed. In an embodiment of the present invention, stimulationtechniques described herein for facilitating transport of diagnosticagents from the systemic blood circulation to the CNS are used inconjunction with techniques described in the '531 patent.

U.S. Pat. No. 6,287,793 to Schenk et al., which is incorporated hereinby reference, describes methods for identifying key diagnosticantibodies and antigens characteristic of a disease state of interest,such as Alzheimer's disease.

U.S. Pat. No. 6,210,895 to Schipper et al., which is incorporated hereinby reference, describes a method for predicting the onset of,diagnosing, and/or prognosticating dementing diseases. The methodcomprises determining the concentration of heme oxygenase-1 (HO-1)and/or a nucleotide sequence encoding HO-1 in tissue obtained from apatient, and comparing said concentration with the correspondingconcentration of HO-1 and/or an HO-1 encoding nucleotide sequence incorresponding tissue obtained from at least one control person. Thetissue is typically plasma, lymphocytes, cerebrospinal fluid orfibroblasts. The method is described as being useful where the dementingdisease is any of Alzheimer's disease, Age-Associated Cognitive Decline,Progressive Supranuclear Palsy, Vascular (i.e., multi-infarct) Dementia,Lewy Body Dementia, Huntington's Disease, Down's syndrome, normalpressure hydrocephalus, corticobasal ganglionic degeneration,multisystem atrophy, head trauma, Creutzfeldt-Jacob disease, viralencephalitis and hypothyroidism. In an embodiment of the presentinvention, stimulation techniques described herein for facilitatingtransport of biochemical agents from the CNS to the systemic bloodcirculation are used in conjunction with techniques described in the'895 patent.

U.S. Pat. No. 6,200,768 to Mandelkow et al., which is incorporatedherein by reference, describes (a) epitopes of the protein which arespecifically occurring in a phosphorylated state in tau protein fromAlzheimer paired helical filaments, (b) protein kinases which areresponsible for the phosphorylation of the amino acids of the tauprotein giving rise to said epitopes, and (c) antibodies specific forsaid epitopes. The patent also describes pharmaceutical compositions forthe treatment or prevention of Alzheimer's disease, diagnosticcompositions and methods for the detection of Alzheimer's disease, andthe use of said epitopes for the generation of antibodies specificallydetecting Alzheimer tau protein. In an embodiment of the presentinvention, stimulation techniques described herein for facilitatingtransport of biochemical agents from the CNS to the systemic bloodcirculation are used in conjunction with techniques described in the'768 patent. For some applications, these techniques facilitateincreased release of said epitopes of the phosphorylated tau into thesystemic circulation, after which a body fluid is analyzed for thepresence of the epitopes or chemical/biological derivatives thereof.

U.S. Pat. No. 6,132,977 to Thompson et al., which is incorporated hereinby reference, describes methods for the immunological identification andquantitation of SNAβ-25 in a biological fluid, especially cerebrospinalfluid and amniotic fluid. The quantitated levels of SNAβ-25 serve as adiagnostic marker for some mental illnesses such as major depression,Alzheimer's disease and schizophrenia. In an embodiment of the presentinvention, stimulation techniques described herein for facilitatingtransport of biochemical agents from the CNS to the systemic bloodcirculation are used in conjunction with techniques described in the'977 patent, in order to release the SNAβ-25 into the systemiccirculation and thereafter analyze body fluid for epitopes and/orchemical/biological derivatives thereof.

U.S. Pat. No. 6,114,175 to Klunk et al., which is incorporated herein byreference, describes methods using amyloid binding compounds which arenon-azo derivatives of Chrysamine G, to identify Alzheimer's brain invivo and to diagnose other pathological conditions characterized byamyloidosis, such as Down's Syndrome. In an embodiment of the presentinvention, stimulation techniques described herein for facilitatingtransport of biochemical agents from the CNS to the systemic bloodcirculation are used in conjunction with techniques described in the'175 patent.

Other patents describe methods for aiding in the diagnosis ofAlzheimer's disease by measuring amyloid-beta peptide levels in a CSFsample of the patient. In an embodiment of the present invention,stimulation techniques described herein for facilitating transport ofdiagnostic agents from the systemic blood circulation to the CNS areused in conjunction with these methods, in order to increase thepermeability of the BBB to transport labeled (e.g., radiolabeled)amyloid-beta mAb or pAb into the CNS and thereafter perform imaging toassess the amount of amyloid-beta peptide. In an embodiment of thepresent invention, stimulation techniques described herein forfacilitating transport of biochemical agents from the CNS to thesystemic blood circulation are used in conjunction with these methods.After transport across the BBB has been facilitated, high levels ofamyloid-beta peptide in body fluid are considered inconsistent with adiagnosis of Alzheimer's disease, while low levels may indicate arationale for further inquiries, and may also indicate an increasedprobability of Alzheimer's disease.

U.S. Pat. No. 6,130,048 to Nixon, which is incorporated herein byreference, describes a method for diagnosing Alzheimer's disease bymeasuring the level of a lysosomal hydrolase or lysosomal proteaseinhibitor in a patient's cerebrospinal fluid. Also described are methodsfor measuring the progression of the disease and for screeningtherapeutic compositions for treating the disease. In an embodiment ofthe present invention, stimulation techniques described herein forfacilitating transport of biochemical agents from the CNS to thesystemic blood circulation are used in conjunction with techniquesdescribed in the '048 patent.

U.S. Pat. No. 6,087,118 to Aronson et al., which is incorporated hereinby reference, describes a method for diagnosing Alzheimer's diseaseusing human blood platelets, wherein the presence or absence offunctioning calcium-dependent potassium channels in blood platelets aredetermined by employing potassium channel blockers such as apamin orcharybdotoxin, the absence of functioning calcium-dependent potassiumchannels indicating a positive diagnosis for Alzheimer's disease. In anembodiment of the present invention, stimulation techniques describedherein for facilitating transport of biochemical agents from the CNS tothe systemic blood circulation are used in conjunction with techniquesdescribed in the '118 patent. It is hypothesized by the inventor of thepresent invention that increasing the permeability of the BBB increasesthe interaction between the intra-cephalic environment and the systemiccirculation, thereby increasing the efficacy and statistical accuracy ofthe method described in the '118 patent.

U.S. Pat. No. 6,071,705 to Wands et al., which is incorporated herein byreference, describes a method for detecting and diagnosing neurologicaldisease or dysfunction, such as Alzheimer's disease and Down's Syndrome,using antibodies against a neurological form of Pancreatic ThreadProtein (nPTP), such antibodies including monoclonal antibodies, acombination of those monoclonal antibodies, or nucleic acid probes. Inan embodiment of the present invention, stimulation techniques describedherein for facilitating transport of diagnostic agents from the systemicblood circulation to the CNS are used in conjunction with techniquesdescribed in the '705 patent, in order to increase the permeability ofthe BBB to transport labeled (e.g., radiolabeled) antibodies of nPTPinto the CNS and thereafter perform imaging to assess the amount of nPTPbound to the labeled antibodies. Alternatively or additionally,stimulation techniques described herein for facilitating transport ofbiochemical agents from the CNS to the systemic blood circulation areused in conjunction with techniques described in the '705 patent, inorder to increase the release of nPTP into the systemic circulation andthereafter sample a body fluid and analyze it for the presence of nPTP.

U.S. Pat. No. 6,001,331 to Caprathe et al., which is incorporated hereinby reference, describes a method of imaging amyloid deposits, andradiolabeled compounds useful in imaging amyloid deposits. In anembodiment of the present invention, stimulation techniques describedherein for facilitating transport of diagnostic agents from the systemicblood circulation to the CNS are used in conjunction with techniquesdescribed in the '331 patent, in order to increase the delivery of theradiolabeled compounds into the CNS, thereby enhancing the contrast ofthe plaque.

U.S. Pat. No. 5,985,581 to Nixon et al., which is incorporated herein byreference, describes a method of diagnosing Alzheimer's diseaseutilizing presenilin-1, whose level is found to be substantiallydecreased in Alzheimer's patients. A CSF sample (ventricular or lumbar)is taken, and the level of presenilin-1 is measured using an immunoassaythat uses antibodies to presenilin-1, to a fragment thereof, or to aspecific amino acid sequence. In an embodiment of the present invention,the antibodies, antibody fragments, or specific amino acid sequencedescribed in the '581 patent are labeled (e.g., radiolabeled) tofacilitate a subsequent imaging procedure for assessing the amount ofbound presenilin-1. The stimulation techniques described herein forfacilitating transport of diagnostic agents from the systemic bloodcirculation to the CNS are used to deliver the labeled compounds to theCNS. In an embodiment of the present invention, stimulation techniquesdescribed herein for facilitating transport of biochemical agents fromthe CNS to the systemic blood circulation are used in conjunction withtechniques described in the '581 patent, in order to increase thepenetration of the abovementioned proteins from the CNS into thesystemic circulation and thereafter analyze a body fluid using themethods and/or diagnostic kits described in the '581 patent. Levels ofthe protein that are higher than a threshold value may indicate theabsence of Alzheimer's disease.

U.S. Pat. No. 5,981,194 to Jefferies et al., which is incorporatedherein by reference, describes methods for using p97 and iron-bindingproteins as diagnostic and therapeutic agents, including for thediagnosis of Alzheimer's disease. The methods are based on evidence thatAlzheimer's patients have elevated levels of elevated levels of p97 intheir serum and cerebrospinal fluid and that p97 levels increase withduration of the disease. The levels of p97 in patient samples may thusbe used to diagnose and to monitor the progression of the disease andthe efficacy of therapeutic treatments for Alzheimer's disease. Evidenceis also presented that microglial cells associated with senile plaquesin Alzheimer's disease express p97 and transferrin receptor. Therefore,p97 and transferrin receptor can be used in the diagnosis of Alzheimer'sDisease. The finding that microglial cells which deposit the amyloidprotein have a high level of proteins which operate in procurement ofiron also suggests methods of treatment of Alzheimer's disease based ondepletion of iron from these cells using substances such as p97,transferrin, and iron chelators, for example, lactoferrin, ferritin, andovotransferrin. In an embodiment of the present invention, stimulationtechniques described herein for facilitating transport of biochemicalagents from the CNS to the systemic blood circulation are used inconjunction with techniques described in the '194 patent. The use ofthese techniques in combination typically enhances the accuracy ofdiagnosis of Alzheimer's disease.

U.S. Pat. No. 5,849,600 to Nixon et al., which is incorporated herein byreference, describes a method for diagnosing Alzheimer's disease in ahuman patient by measuring the amount of p33 present in a biologicalsample, such as a ventricular or lumbar CSF sample, or brain tissuehomogenate. In an embodiment of the present invention, the stimulationtechniques described herein are used to facilitate transport of alabeled (e.g., radiolabeled) anti-p33 mAb or pAb from the systemiccirculation to the CNS. An imaging procedure is subsequently performedto evaluate the amount of p33 protein in the CNS. In an embodiment ofthe present invention, stimulation techniques described herein forfacilitating transport of biochemical agents from the CNS to thesystemic blood circulation are used in conjunction with techniquesdescribed in the '600 patent, in order to increase the penetration ofthe abovementioned protein from the CNS into the systemic circulation.Thereafter a body fluid is analyzed using the methods and/or diagnostickits described in the '600 patent. Levels of the protein that are higherthan a threshold value may indicate the presence of Alzheimer's disease.

U.S. Pat. No. 5,833,988 to Friden, which is incorporated herein byreference, describes a method for delivering a neuropharmaceutical ordiagnostic agent across the BBB to the brain. The method comprisesadministering to the host a therapeutically effective amount of anantibody-neuropharmaceutical or diagnostic agent conjugate wherein theantibody is reactive with a transferrin receptor. In an embodiment ofthe present invention, the stimulation techniques described herein areused to facilitate transport of an agent described in the '988 patentfrom the systemic circulation to the CNS. An imaging procedure issubsequently performed to evaluate the amount of a ligand of the agentin the CNS.

U.S. Pat. No. 5,830,670 to de la Monte et al., which is incorporatedherein by reference, describes a method for diagnosing Alzheimer'sdisease, neuroectodermal tumors, malignant astrocytomas, andglioblastomas, by identifying recombinant hosts and vectors whichcontain the genes coding for neuronal thread proteins (NTPs) associatedwith these conditions. Specific targeted NTPs have molecular weights ofabout 8 kDa, about 14 kDa, about 17 kDa, about 21 kDa, about 26 kDa orabout 42 kDa. In an embodiment of the present invention, the stimulationtechniques described herein are used to facilitate transport of alabeled (e.g., radiolabeled) antibody against an NTP from the systemiccirculation to the CNS. An imaging procedure is subsequently performedto evaluate the amount of the NTP in the CNS. In an embodiment of thepresent invention, stimulation techniques described herein forfacilitating transport of biochemical agents from the CNS to thesystemic blood circulation are used in conjunction with techniquesdescribed in the '670 patent, in order to increase the penetration ofthe abovementioned protein from the CNS into the systemic circulation.Thereafter in vivo or in vitro analysis of body fluid is performed,typically using a diagnostic kit. Levels of the protein that are higherthan a threshold value may indicate the presence of Alzheimer's diseaseor other conditions described in the '670 patent.

In an embodiment of the present invention, stimulation techniquesdescribed herein are used to facilitate a diagnosis of brain tumors(primary and secondary (metastatic) neoplasms in the brain). Suchstimulation typically facilitates the transfer from the systemiccirculation to the CNS of a labeled (e.g., radiolabeled) diagnosticagent, which may be specific for the neoplasm to be diagnosed, for agroup of neoplasms, or generally for a pathologic state in the CNS.

For example, these stimulation techniques may be used to diagnosisgliomas. Gliomas often overexpress a receptor for interleukin 13(IL-13). Because interleukins have large molecular sizes (typically, tenof kilodaltons), they generally penetrate the CNS poorly under a widerange of physiological conditions. In conjunction with administration oflabeled IL-13 into the systemic circulation, an MTS is stimulated,allowing the IL-13 to pass into the CNS, where the IL-13 typicallyconcentrates in tumor locations. Such concentration is detected using animaging procedure. This approach typically represents a relativelylow-risk and highly disease-specific approach to diagnosing such tumors.

Another example is the use of labeled (e.g., radiolabeled) anti-HER2 mAbor pAb for imaging of breast cancer metastases in the brain. HER2 is aprotein over-expressed on the malignant cell outer membrane in asignificant percentage of patients with breast cancer. The permeabilityof the BBB is increased using the stimulation techniques describedherein, in conjunction with administration of labeled anti-HER2 mAb ormAb and performance of an imaging procedure. This approach typicallyrepresents a relatively low-risk and highly disease-specific approach todiagnosing such metastases.

In an embodiment, methods are used for aiding the diagnosis of braintumors or screening for brain tumors. Typically, these methods includeusing labeled interleukins, anti-cancer-cells mAb/pAb or other possiblemarkers of neoplasms in conjunction with an imaging procedures. In anembodiment of the present invention, stimulation techniques describedherein for facilitating transport of diagnostic agents from the systemicblood circulation to the CNS are used to transport labeled (e.g.,radiolabeled) amyloid-beta mAb or pAb into the CNS, and a subsequentimaging procedure is performed.

In an embodiment of the present invention, the stimulation techniquesdescribed herein are used to facilitate increased release ofdisease-related agents (e.g., proteins, DNA fragments, etc.) from theCNS into the systemic circulation and body tissues. To diagnose braintumors, these techniques are used to facilitate the transport of markersof the central malignant process (e.g. glioma) from the CNS to thesystemic circulation, where they are detected using a suitable bioassay.

For some applications, the diagnostic techniques described herein areused at more than one point in time in order to indicate the possibleprogression of the CNS condition being diagnosed.

Some existing and proposed diagnostic techniques use a sample of CSF forbiochemical analysis. In an embodiment of the present invention,stimulation techniques described herein are used to increase transportof biochemical markers from the CSF to the systemic circulation as analternative to direct sampling of the CSF.

“Diagnosis,” as used in the present patent application, including theclaims, is to be understood as comprising the art or act of recognizingthe presence of disease from its signs or symptoms, deciding as to thecharacter (e.g., stage) of a disease, screening for disease, and/orpredicting the onset of disease. Diagnosis may be performed in vivo orin vitro, as appropriate. Diagnosis may comprise a combination ofdiagnostic procedures. For example, the permeability of the BBB may beincreased in combination with taking a blood sample and analyzing it forthe presence of a biochemical marker of a CNS neoplastic process, andperforming PET imaging for a mAb or pAb to a protein that is indicativeof a neoplastic process.

Whereas some embodiments of the present invention are described hereinwith respect to enhancing permeability of the BBB so as to facilitatepassage of molecules from the systemic circulation to brain tissue of apatient, this is by way of illustration and not limitation. In otherembodiments, analogous techniques are utilized so as to facilitateenhanced clearance of molecules from brain tissue to the systemiccirculation. For some applications, this enhanced clearance is utilizedto facilitate a diagnostic procedure, for example by means of an imagingmodality or a blood sample taken during or subsequent to increased BBBpermeability. For other applications, the enhanced clearance ofmolecules is a goal in and of itself, for example in order to facilitateclearance of toxins from the brain.

Techniques described in this application may be practiced in combinationwith methods and apparatus described in one or more of the followingpatent applications, which are assigned to the assignee of the presentpatent application and are incorporated herein by reference:

-   -   PCT Publication WO 01/85094, filed May 7, 2001, entitled,        “Method and apparatus for stimulating the sphenopalatine        ganglion to modify properties of the BBB and cerebral blood        flow,” and U.S. Patent Application Publication 2004/0015068 to        Shalev and Gross    -   U.S. Provisional Patent Application 60/364,451, filed Mar. 15,        2002, entitled, “Applications of stimulating the sphenopalatine        ganglion (SPG)”    -   U.S. Provisional Patent Application 60/368,657, filed Mar. 28,        2002, entitled, “SPG Stimulation”    -   U.S. Provisional Patent Application 60/376,048, filed Apr. 25,        2002, entitled, “Methods and apparatus for modifying properties        of the BBB and cerebral circulation by using the neuroexcitatory        and/or neuroinhibitory effects of odorants on nerves in the        head”    -   U.S. Provisional Patent Application 60/388,931, filed Jun. 14,        2002, entitled “Methods and systems for management of        Alzheimer's disease”    -   U.S. Provisional Patent Application 60/400,167, filed Jul. 31,        2002, entitled, “Delivering compounds to the brain by modifying        properties of the BBB and cerebral circulation,” and PCT        Publication WO 04/010923 to Gross et al.    -   U.S. Provisional Patent Application 60/426,180, filed Nov. 14,        2002, entitled, “Surgical tools and techniques for        sphenopalatine ganglion stimulation,” and PCT Publication WO        04/043218 to Gross et al.    -   U.S. Provisional Patent Application 60/426,182, filed Nov. 14,        2002, entitled, “Stimulation circuitry and control of electronic        medical device,” and PCT Publication WO 04/044947 to Gross et        al.    -   U.S. patent application Ser. No. 10/294,310, filed Nov. 14,        2002, entitled, “SPG stimulation for treating eye pathologies,”        and PCT Publication WO 04/043217 to Gross et al.    -   U.S. patent application Ser. No. 10/294,343, filed Nov. 14,        2002, entitled, “Administration of anti-inflammatory drugs into        the CNS,” and PCT Publication WO 04/043334 to Shalev    -   U.S. Provisional Patent Application 60/426,181, filed Nov. 14,        2002, entitled, “Stimulation for treating ear pathologies,” and        PCT Publication WO 04/045242 to Shalev et al.    -   U.S. Provisional Patent Application 60/448,807, filed Feb. 20,        2003, entitled, “Stimulation for treating autoimmune-related        disorders of the CNS”    -   U.S. Provisional Patent Application 60/461,232 to Gross et al.,        filed Apr. 8, 2003, entitled, “Treating abnormal conditions of        the mind and body by modifying properties of the blood-brain        barrier and cephalic blood flow”.

In particular, techniques of electrical signal application described inthe above list of patent applications may be used together with orinstead of odorant presentation. Thus, applications described hereinwhich utilize odorant presentation may instead use electrical signalapplication to achieve generally similar results to those achievedthrough odorant presentation.

It is to be understood that the term “blood brain barrier (BBB),” asused in the context of the present patent application and in the claims,applies to the barrier between the systemic circulation and the brain,as well as to the barrier between the systemic circulation and a tumorin the brain (sometimes referred to as the “blood tumor barrier”).

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description. For example, elementswhich are shown in a figure to be housed within one integral unit may,for some applications, be disposed in a plurality of distinct units.Similarly, apparatus for communication and power transmission which areshown to be coupled in a wireless fashion may be, alternatively, coupledin a wired fashion, and apparatus for communication and powertransmission which are shown to be coupled in a wired fashion may be,alternatively, coupled in a wireless fashion. In addition, it is to beunderstood that the scope of the present invention includes apparatusfor carrying out methods described and/or claimed herein, and alsoincludes methods corresponding to apparatus described and/or claimedherein.

1. A method for facilitating a diagnosis of a condition of a subject,comprising: applying a current to a site of the subject selected fromthe list consisting of: a sphenopalatine ganglion (SPG) of the subject,and a neural tract originating in or leading to the SPG; configuring thecurrent to increase conductance of molecules from brain tissue of thesubject through a blood brain barrier (BBB) of the subject into asystemic blood circulation of the subject; and sensing a quantity of themolecules from a site outside of the brain of the subject, followinginitiation of application of the current.
 2. The method according toclaim 1, wherein sensing the quantity of the molecules comprisessampling a fluid of the subject selected from the list consisting of:blood, plasma, serum, ascites fluid, and urine.
 3. The method accordingto claim 1, comprising determining a diagnostically-relevant parameterresponsive to sensing the quantity of the molecules.
 4. The methodaccording to claim 1, comprising administering ahyperosmolarity-inducing agent to the subject at a dosage sufficient toaugment an increase in conductance of the molecules caused by theapplication of the current.
 5. The method according to claim 1,comprising inducing a state of dehydration of the subject, of an extentsufficient to augment an increase in conductance of the molecules causedby the application of the current.
 6. The method according to claim 1,comprising administering an agent to the subject that modulatessynthesis or metabolism of nitric-oxide (NO) in blood vessels of thebrain, at a dosage sufficient to augment an increase in conductance ofthe molecules caused by the application of the current.
 7. The methodaccording to claim 1, wherein applying the current comprises implantingan electrode at the site, designated to remain in the subject for aperiod greater than about one month.
 8. The method according to claim 1,wherein applying the current comprises implanting an electrode at thesite, designated to remain in the subject for a period less than aboutone week.
 9. The method according to claim 1, wherein applying thecurrent comprises implanting a control unit in a nasal cavity of thesubject.
 10. The method according to claim 1, wherein applying thecurrent comprises implanting a control unit at a lower side of a bonypalate of the subject.
 11. The method according to claim 1, whereinapplying the current comprises implanting one or more electrodes in anasal cavity of the subject.
 12. The method according to claim 11,wherein implanting comprises inserting a flexible electrode through anostril of the subject.
 13. A method for facilitating a diagnosis of acondition of a central nervous system (CNS) of a subject, comprising:stimulating sphenopalatine ganglion (SPG)-related tissue of the subjectby applying an electrical signal to the SPG-related tissue, theSPG-related tissue selected from: an SPG of the subject and nerve fibersof the subject which are directly anatomically connected to the SPG; andconfiguring the stimulation so as to cause an increase in molecularpassage between the CNS and another body compartment of the subject, soas to facilitate the diagnosis of the CNS condition.
 14. The methodaccording to claim 13, comprising measuring a constituent of the otherbody compartment.
 15. The method according to claim 14, whereinstimulating the SPG-related tissue comprises directly stimulating theSPG.
 16. The method according claim 14, wherein the other bodycompartment includes a systemic blood circulation of the subject, andwherein configuring the stimulation comprises configuring thestimulation so as to cause the increase in molecular passage between theCNS and the systemic blood circulation.
 17. The method according toclaim 14, wherein the other body compartment includes plasma of thesubject, and wherein configuring the stimulation comprises configuringthe stimulation so as to cause the increase in molecular passage betweenthe CNS and the plasma.
 18. The method according to claim 14, whereinthe other body compartment includes serum of the subject, and whereinconfiguring the stimulation comprises configuring the stimulation so asto cause the increase in molecular passage between the CNS and theserum.
 19. The method according to claim 14, wherein the other bodycompartment is ascites of the subject, and wherein configuring thestimulation comprises configuring the stimulation so as to cause theincrease in molecular passage between the CNS and the ascites.
 20. Themethod according to claim 14, wherein the CNS condition includesParkinson's disease, and wherein configuring the stimulation comprisesconfiguring the stimulation so as to facilitate the diagnosis of theParkinson's disease.
 21. The method according to claim 14, wherein theCNS condition includes epilepsy, and wherein configuring the stimulationcomprises configuring the stimulation so as to facilitate the diagnosisof the epilepsy.
 22. The method according to claim 14, wherein the CNScondition includes amyotrophic lateral sclerosis (ALS), and whereinconfiguring the stimulation comprises configuring the stimulation so asto facilitate the diagnosis of the ALS.
 23. The method according toclaim 14, wherein the CNS condition includes multiple sclerosis (MS),and wherein configuring the stimulation comprises configuring thestimulation so as to facilitate the diagnosis of the MS.
 24. The methodaccording to claim 14, wherein stimulating the SPG-related tissuecomprises implanting an electrode at the site, designated to remain inthe subject for a period greater than about one month.
 25. The methodaccording to claim 14, wherein stimulating the SPG-related tissuecomprises implanting an electrode at the site, designated to remain inthe subject for a period less than about one week.
 26. The methodaccording to claim 14, wherein stimulating the SPG-related tissuecomprises implanting a control unit in a nasal cavity of the subject.27. The method according to claim 14, wherein stimulating theSPG-related tissue comprises implanting a control unit at a lower sideof a bony palate of the subject.
 28. The method according to claim 14,comprising correlating an abnormal concentration of the constituent to apathology of the CNS condition.
 29. The method according to claim 14,wherein the constituent is selected from the group consisting of: aprotein, a honnone, an antibody, an electrolyte, a neuropeptide, and anenzyme, and wherein measuring the constituent comprises measuring theselected constituent.
 30. A method for facilitating a diagnosis of acondition of a central nervous system (CNS) of a subject, comprising:stimulating sphenopalatine ganglion (SPG)-related tissue of the subjectby applying an electrical signal to the SPG-related tissue, theSPG-related tissue selected from: an SPG of the subject and nerve fibersof the subject which are directly anatomically connected to the SPG; andconfiguring the stimulation so as to cause an increase in molecularpassage between cerebrospinal fluid (CSF) of the subject and anotherbody fluid of the subject, so as to facilitate the diagnosis of the CNScondition.
 31. The method according to claim 30, comprising measuring aconstituent of the other body fluid.
 32. The method according to claim31, wherein stimulating the SPG-related tissue comprises directlystimulating the SPG.
 33. The method according to claim 31, comprisingcorrelating an abnormal concentration of the constituent to a pathologyof the CNS condition.
 34. The method according to claim 31, wherein theconstituent is selected from the group consisting of: a protein, ahormone, an antibody, an electrolyte, a neuropeptide, and an enzyme, andwherein measuring the constituent comprises measuring the selectedconstituent.
 35. The method according to claim 31, wherein the otherbody fluid is selected from the list consisting of: whole blood, plasma,serum, and ascites, and wherein measuring the constituent comprisessampling the selected fluid.
 36. The method according to claim 31,wherein measuring the constituent comprises extracting the other bodyfluid from tissue of the subject.
 37. The method according to claim 31,wherein applying the current comprises implanting an electrode at thesite, designated to remain in the subject for a period greater thanabout one month.
 38. The method according to claim 31, wherein applyingthe current comprises implanting an electrode at the site, designated toremain in the subject for a period less than about one week.
 39. Themethod according to claim 31, wherein applying the current comprisesimplanting a control unit in a nasal cavity of the subject.
 40. Themethod according to claim 31, wherein applying the current comprisesimplanting a control unit at a lower side of a bony palate of thesubject.
 41. The method according to claim 31, wherein measuring theconstituent comprises measuring a plurality of constituents.
 42. Themethod according to claim 41, comprising determining a diagnostic resultaccording to the interrelation between concentrations of theconstituents.
 43. A method for facilitating a diagnosis of a conditionof a central nervous system (CNS) of a subject, comprising: stimulatingsphenopalatine ganglion (SPG)-related tissue of the subject by applyingan electrical signal to the SPG-related tissue, the SPG-related tissueselected from: an SPG of the subject and nerve fibers of the subjectwhich are directly anatomically connected to the SPG; and configuringthe stimulation so as to cause an increase in molecular passage betweencerebrospinal fluid (CSF) of the subject and a tissue of the subject, soas to facilitate a diagnosis of the CNS condition.
 44. The methodaccording claim 43, comprising measuring a constituent of the tissue.45. The method according to claim 44, wherein stimulating theSPG-related tissue comprises directly stimulating the SPG.
 46. Themethod according to claim 44, comprising correlating an abnormalconcentration of the constituent to a pathology of the CNS condition.47. The method according to claim 44, wherein the constituent isselected from the group consisting of: a protein, a hormone, anantibody, an electrolyte, a neuropeptide, and an enzyme, and whereinmeasuring the constituent comprises measuring the selected constituent.48. The method according to claim 44, wherein measuring the constituentcomprises measuring a plurality of constituents of the tissue.
 49. Themethod according to claim 48, comprising determining a diagnostic resultaccording to the interrelation between concentrations of theconstituents of the tissue.
 50. A method for facilitating a diagnosis ofa condition of a central nervous system (CNS) of a subject, comprising:applying an electrical signal to at least one site of the subject, thesite selected from the list consisting of: a sphenopalatine ganglion(SPG) of the subject, an anterior ethmoidal nerve of the subject, aposterior ethmoidal nerve of the subject, a communicating branch betweenan anterior ethmoidal nerve and a retro-orbital branch of an SPG of thesubject, a communicating branch between a posterior ethmoidal nerve anda retro-orbital branch of an SPG of the subject, a greater palatinenerve of the subject, a lesser palatine nerve of the subject, asphenopalatine nerve of the subject, a communicating branch between amaxillary nerve and an SPG of the subject, a nasopalatine nerve of thesubject, a posterior nasal nerve of the subject, an infraorbital nerveof the subject, an otic ganglion of the subject, an afferent fiber goinginto the otic ganglion of the subject, an efferent fiber going out ofthe otic ganglion of the subject, a vidian nerve of the subject, agreater superficial petrosal nerve of the subject, and a lesser deeppetrosal nerve of the subject; and configuring the signal so as to causean increase in molecular passage between the CNS and another bodycompartment of the subject, so as to facilitate a diagnosis of the CNScondition.
 51. The method according claim 50, comprising measuring aconstituent of the other body compartment.
 52. A method for facilitatinga diagnosis of a condition of a central nervous system (CNS) of asubject, comprising: applying an electrical signal to at least one siteof the subject, the site selected from the list consisting of: asphenopalatine ganglion (SPG) of the subject, an anterior ethmoidalnerve of the subject, a posterior ethmoidal nerve of the subject, acommunicating branch between an anterior ethmoidal nerve and aretro-orbital branch of an SPG of the subject, a communicating branchbetween a posterior ethmoidal nerve and a retro-orbital branch of an SPGof the subject, a greater palatine nerve of the subject, a lesserpalatine nerve of the subject, a sphenopalatine nerve of the subject, acommunicating branch between a maxillary nerve and an SPG of thesubject, a nasopalatine nerve of the subject, a posterior nasal nerve ofthe subject, an infraorbital nerve of the subject, an otic ganglion ofthe subject, an afferent fiber going into the otic ganglion of thesubject, an efferent fiber going out of the otic ganglion of thesubject, a vidian nerve of the subject, a greater superficial petrosalnerve of the subject, and a lesser deep petrosal nerve of the subject;and configuring the signal so as to cause an increase in molecularpassage between cerebrospinal fluid (CSF) of the subject and anotherbody fluid of the subject, so as to facilitate a diagnosis of the CNScondition.
 53. The method according claim 52, comprising measuring aconstituent of the other body fluid.
 54. A method for facilitating adiagnosis of a condition of a central nervous system (CNS) of a subject,comprising: applying an electrical signal to at least one site of thesubject, the site selected from the list consisting of: a sphenopalatineganglion (SPG) of the subject, an anterior ethmoidal nerve of thesubject, a posterior ethmoidal nerve of the subject, a communicatingbranch between an anterior ethmoidal nerve and a retro-orbital branch ofan SPG of the subject, a communicating branch between a posteriorethmoidal nerve and a retro-orbital branch of an SPG of the subject, agreater palatine nerve of the subject, a lesser palatine nerve of thesubject, a sphenopalatine nerve of the subject, a communicating branchbetween a maxillary nerve and an SPG of the subject, a nasopalatinenerve of the subject, a posterior nasal nerve of the subject, aninfraorbital nerve of the subject, an otic ganglion of the subject, anafferent fiber going into the otic ganglion of the subject, an efferentfiber going out of the otic ganglion of the subject, a vidian nerve ofthe subject, a greater superficial petrosal nerve of the subject, and alesser deep petrosal nerve of the subject; and configuring the signal soas to cause an increase in molecular passage between cerebrospinal fluid(CSF) of the subject and a tissue of the subject, so as to facilitate adiagnosis of the CNS condition.
 55. The method according claim 54,comprising measuring a constituent of the tissue.
 56. A method forfacilitating a diagnosis of a condition of a central nervous system(CNS) of a subject, the method comprising: stimulating at least one siteof the subject by applying an electrical current to the site, the siteselected from the list consisting of: a sphenopalatine ganglion (SPG) ofthe subject, an anterior ethmoidal nerve of the subject, a posteriorethmoidal nerve of the subject, a communicating branch between theanterior ethmoidal nerve and the SPG, a communicating branch between theposterior ethmoidal nerve and the SPG, a nerve of the pterygoid canal ofthe subject, a greater palatine nerve of the subject, a lesser palatinenerve of the subject, a sphenopalatine nerve of the subject, acommunicating branch between a maxillary nerve of the subject and theSPG, a nasopalatine nerve of the subject, a posterior nasal nerve of thesubject, an infraorbital nerve of the subject, an otic ganglion of thesubject, an afferent fiber going into the otic ganglion, and an efferentfiber going out of the otic ganglion; configuring the stimulation so asto cause an increase in molecular passage between the CNS and anotherbody compartment of the subject; taking a sample from the bodycompartment; and determining a level of a constituent of the sample, soas to facilitate the diagnosis of the CNS condition.
 57. The methodaccording to claim 56, wherein the CNS condition includes aneurodegenerative condition, and wherein determining the level of theconstituent comprises determining the level of the constituent so as tofacilitate the diagnosis of the neurodegenerative condition.
 58. Themethod according to claim 56, wherein the CNS condition includes aneoplastic process, and wherein determining the level of the constituentcomprises determining the level of the constituent so as to facilitatethe diagnosis of the neoplastic process.
 59. The method according toclaim 56, wherein the CNS condition is selected from the list consistingof: an immune-related disorder and an autoimmune-related disorder, andwherein determining the level of the constituent comprises determiningthe level of the constituent so as to facilitate the diagnosis of theselected condition.
 60. The method according to claim 56, wherein theCNS condition includes a CNS inflammatory process, and whereindetermining the level of the constituent comprises determining the levelof the constituent so as to facilitate the diagnosis of the CNSinflammatory process.
 61. The method according to claim 56, comprisinginterpreting a low value of the level as indicative of an increasedlikelihood that the subject suffers from the CNS condition.
 62. Themethod according to claim 61, comprising interpreting a high value ofthe level as indicative of a decreased likelihood that the subjectsuffers from the CNS condition.
 63. The method according to claim 61,wherein the body compartment includes a systemic blood circulation ofthe subject, and wherein configuring the stimulation comprisesconfiguring the stimulation so as to cause the increase in molecularpassage between the CNS and the systemic blood circulation.
 64. Themethod according to claim 61, wherein the body compartment includesplasma of the subject, and wherein configuring the stimulation comprisesconfiguring the stimulation so as to cause the increase in molecularpassage between the CNS and the plasma.
 65. The method according toclaim 61, wherein the body compartment includes serum of the subject,and wherein configuring the stimulation comprises configuring thestimulation so as to cause the increase in molecular passage between theCNS and the serum.
 66. The method according to claim 61, wherein thebody compartment is ascites of the subject, and wherein configuring thestimulation comprises configuring the stimulation so as to cause theincrease in molecular passage between the CNS and the ascites.
 67. Themethod according to claim 61, wherein the site includes the SPG, andwherein stimulating the site comprises stimulating the SPG.
 68. Themethod according to claim 61 wherein the CNS condition includesAlzheimer's disease, and wherein interpreting the low value comprisesinterpreting the low value as indicative of the increased likelihoodthat the subject suffers from Alzheimer's disease.
 69. The methodaccording to claim 68, wherein the constituent includes amyloid-betapeptide, and wherein determining the level of the constituent comprisesdetermining the level of the amyloid-beta peptide.
 70. The methodaccording to claim 68, wherein the constituent includes presenilin-1,and wherein determining the level of the constituent comprisesdetermining the level of the presenilin-1.
 71. A method for facilitatinga diagnosis of a condition of a central nervous system (CNS) of asubject, the method comprising: stimulating at least one site of thesubject selected from the list consisting of: a sphenopalatine ganglion(SPG) of the subject, an anterior ethmoidal nerve of the subject, aposterior ethmoidal nerve of the subject, a communicating branch betweenthe anterior ethmoidal nerve and the SPG, a communicating branch betweenthe posterior ethmoidal nerve and the SPG, a nerve of the pterygoidcanal of the subject, a greater palatine nerve of the subject, a lesserpalatine nerve of the subject, a sphenopalatine nerve of the subject, acommunicating branch between a maxillary nerve of the subject and theSPG, a nasopalatine nerve of the subject, a posterior nasal nerve of thesubject, an infraorbital nerve of the subject, an otic ganglion of thesubject, an afferent fiber going into the otic ganglion, and an efferentfiber going out of the otic ganglion; configuring the stimulation so asto cause an increase in molecular passage between the CNS and anotherbody compartment of the subject; taking a sample from the bodycompartment; and determining a level of a constituent of the sample, soas to facilitate the diagnosis of the CNS condition.
 72. The methodaccording to claim 71, wherein the CNS condition includes aneurodegenerative condition, and wherein determining the level of theconstituent comprises determining the level of the constituent so as tofacilitate the diagnosis of the neurodegenerative condition.
 73. Themethod according to claim 71, wherein the CNS condition includes aneoplastic process, and wherein determining the level of the constituentcomprises determining the level of the constituent so as to facilitatethe diagnosis of the neoplastic process.
 74. The method according toclaim 71, wherein the CNS condition is selected from the list consistingof: an immune-related disorder and an autoimmune-related disorder, andwherein determining the level of the constituent comprises determiningthe level of the constituent so as to facilitate the diagnosis of theselected condition.
 75. The method according to claim 71, wherein theCNS condition includes a CNS inflammatory process, and whereindetermining the level of the constituent comprises determining the levelof the constituent so as to facilitate the diagnosis of the CNSinflammatory process.
 76. The method according to claim 71, comprisinginterpreting a low value of the level as indicative of an increasedlikelihood that the subject suffers from the CNS condition.
 77. Themethod according to claim 76, comprising interpreting a high value ofthe level as indicative of a decreased likelihood that the subjectsuffers from the CNS condition.
 78. The method according to claim 76,wherein stimulating comprises applying magnetic stimulation to the site.79. The method according to claim 76, wherein stimulating comprisesapplying electromagnetic stimulation to the site.
 80. The methodaccording to claim 76, wherein stimulating comprises applying chemicalstimulation to the site.
 81. The method according to claim 76, whereinstimulating comprises applying mechanical stimulation to the site. 82.The method according to claim 76, wherein the body compartment includesa systemic blood circulation of the subject, and wherein configuring thestimulation comprises configuring the stimulation so as to cause theincrease in molecular passage between the CNS and the systemic bloodcirculation.
 83. The method according to claim 76, wherein the bodycompartment includes plasma of the subject, and wherein configuring thestimulation comprises configuring the stimulation so as to cause theincrease in molecular passage between the CNS and the plasma.
 84. Themethod according to claim 76, wherein the body compartment includesserum of the subject, and wherein configuring the stimulation comprisesconfiguring the stimulation so as to cause the increase in molecularpassage between the CNS and the serum.
 85. The method according to claim76, wherein the body compartment is ascites of the subject, and whereinconfiguring the stimulation comprises configuring the stimulation so asto cause the increase in molecular passage between the CNS and theascites.
 86. The method according to claim 76, wherein the site includesthe SPG, and wherein stimulating the site comprises stimulating the SPG.87. The method according to claim 76, wherein the CNS condition includesAlzheimer's disease, and wherein interpreting the low value comprisesinterpreting the low value as indicative of the increased likelihoodthat the subject suffers from Alzheimer's disease.
 88. The methodaccording to claim 87, wherein the constituent includes amyloid-betapeptide, and wherein determining the level of the constituent comprisesdetermining the level of the amyloid-beta peptide.
 89. The methodaccording to claim 87, wherein the constituent includes presenilin-1,and wherein determining the level of the constituent comprisesdetermining the level of the presenilin-1.
 90. A method for treating acondition of a central nervous system (CNS) of a subject, comprising:applying a current to a site of the subject selected from the listconsisting of: a sphenopalatine ganglion (SPG) of the subject, and aneural tract originating in or leading to the SPG; configuring thecurrent to increase clearance of molecules from brain tissue of thesubject through a blood brain barrier (BBB) of the subject into asystemic blood circulation of the subject, so as to treat the CNScondition.
 91. The method according to claim 90, wherein the moleculesinclude a toxin, and wherein configuring the current comprisesconfiguring the current to increase the clearance of the toxin from thebrain tissue, so as to treat the CNS condition.
 92. The method accordingto claim 90, wherein applying the current comprises implanting anelectrode at the site, designated to remain in the subject for a periodgreater than about one month.
 93. The method according to claim 90,wherein applying the current comprises implanting an electrode at thesite, designated to remain in the subject for a period less than aboutone week.
 94. The method according to claim 90, wherein applying thecurrent comprises implanting a control unit in a nasal cavity of thesubject.
 95. The method according to claim 90, wherein applying thecurrent comprises implanting a control unit at a lower side of a bonypalate of the subject.
 96. A method for treating a condition of acentral nervous system (CNS) of a subject, comprising: stimulatingsphenopalatine ganglion (SPG)-related tissue of the subject by applyingan electrical signal to the SPG-related tissue, the SPG-related tissueselected from: an SPG of the subject and nerve fibers of the subjectwhich are directly anatomically connected to the SPG; and configuringthe stimulation so as to cause an increase in clearance of a neurotoxiccompound from a brain of the subject through a blood brain barrier (BBB)of the subject to a systemic blood circulation of the subject, so as totreat the CNS condition.
 97. The method according to claim 96, whereinstimulating the SPG-related tissue comprises directly stimulating theSPG.
 98. A method for treating a condition of a central nervous system(CNS) of a subject, comprising: stimulating sphenopalatine ganglion(SPG)-related tissue of the subject by presenting an odorant to an airpassage of the subject, the SPG-related tissue selected from: an SPG ofthe subject and nerve fibers of the subject which are directlyanatomically connected to the SPG; and configuring the stimulation so asto cause an increase in clearance of a neurotoxic compound from a brainof the subject through a blood brain barrier (BBB) of the subject to asystemic blood circulation of the subject, so as to treat the CNScondition.
 99. A method for treating a condition of a central nervoussystem (CNS) of a subject, comprising: stimulating sphenopalatineganglion (SPG)-related tissue of the subject by applying an electricalsignal to the SPG-related tissue, the SPG-related tissue selected from:an SPG of the subject and nerve fibers of the subject which are directlyanatomically connected to the SPG; and configuring the stimulation so asto cause an increase in clearance of a neurotoxic compound fromcerebrospinal fluid (CSF) of the subject through a blood brain barrier(BBB) of the subject to a systemic blood circulation of the subject, soas to treat the CNS condition.
 100. The method according to claim 99,wherein stimulating the SPG-related tissue comprises directlystimulating the SPG.
 101. A method for treating a condition of a centralnervous system (CNS) of a subject, comprising: stimulatingsphenopalatine ganglion (SPG)-related tissue of the subject bypresenting an odorant to an air passage of the subject, the SPG-relatedtissue selected from: an SPG of the subject and nerve fibers of thesubject which are directly anatomically connected to the SPG; andconfiguring the stimulation so as to cause an increase in clearance of aneurotoxic compound from cerebrospinal fluid (CSF) of the subjectthrough a blood brain barrier (BBB) of the subject to a systemic bloodcirculation of the subject, so as to treat the CNS condition. 102.Apparatus for facilitating a diagnosis of a condition of a subject,comprising a stimulator adapted to: apply a current to a site of thesubject selected from the list consisting of: a sphenopalatine ganglion(SPG) of the subject, and a neural tract originating in or leading tothe SPG, and configure the current to increase conductance of moleculesfrom brain tissue of the subject through a blood brain barrier (BBB) ofthe subject into a systemic blood circulation of the subject, so as tofacilitate the diagnosis of the condition.
 103. The apparatus accordingto claim 102, wherein the stimulator is adapted to directly stimulatethe SPG.
 104. The apparatus according to claim 102, wherein theapparatus is adapted to measure a constituent of the other bodycompartment.
 105. Apparatus for facilitating a diagnosis of a conditionof a central nervous system (CNS) of a subject, comprising a stimulatoradapted to: stimulate sphenopalatine ganglion (SPG)-related tissue ofthe subject by applying an electrical signal to the SPG-related tissue,the SPG-related tissue selected from: an SPG of the subject and nervefibers of the subject which are directly anatomically connected to theSPG, and configure the stimulation so as to cause an increase inmolecular passage between the CNS and another body compartment of thesubject, so as to facilitate the diagnosis of the CNS condition. 106.The apparatus according to claim 105, wherein the stimulator is adaptedto directly stimulate the SPG.
 107. The apparatus according to claim105, wherein the apparatus is adapted to measure a constituent of theother body compartment.
 108. The apparatus according to claim 107,wherein the other body compartment includes a systemic blood circulationof the subject, and wherein the apparatus is adapted to measure theconstituent of the systemic blood circulation.
 109. The apparatusaccording to claim 107, wherein the other body compartment includesplasma of the subject, and wherein the apparatus is adapted to measurethe constituent of the plasma.
 110. The apparatus according to claim107, wherein the other body compartment includes serum of the subject,and wherein the apparatus is adapted to measure the constituent of theserum.
 111. The apparatus according to claim 107, wherein the other bodycompartment is ascites of the subject, and wherein the apparatus isadapted to measure the constituent of the ascites.
 112. Apparatus forfacilitating a diagnosis of a condition of a central nervous system(CNS) of a subject, comprising a stimulator adapted to: stimulatesphenopalatine ganglion (SPG)-related tissue of the subject by applyingan electrical signal to the SPG-related tissue, the SPG-related tissueselected from: an SPG of the subject and nerve fibers of the subjectwhich are directly anatomically connected to the SPG, and configure thestimulation so as to cause an increase in molecular passage betweencerebrospinal fluid (CSF) of the subject and another body fluid of thesubject, so as to facilitate the diagnosis of the CNS condition. 113.The apparatus according to claim 112, wherein the stimulator is adaptedto directly stimulate the SPG.
 114. The apparatus according to claim112, wherein the apparatus is adapted to measure a constituent of theother body fluid.
 115. Apparatus for facilitating a diagnosis of acondition of a central nervous system (CNS) of a subject, comprising astimulator adapted to: stimulate sphenopalatine ganglion (SPG)-relatedtissue of the subject by applying an electrical signal to theSPG-related tissue, the SPG-related tissue selected from: an SPG of thesubject and nerve fibers of the subject which are directly anatomicallyconnected to the SPG, and configure the stimulation so as to cause anincrease in molecular passage between cerebrospinal fluid (CSF) of thesubject and a tissue of the subject, so as to facilitate the diagnosisof the CNS condition.
 116. The apparatus according to claim 115, whereinthe apparatus is adapted to directly stimulate the SPG.
 117. Theapparatus according to claim 115, wherein the apparatus is adapted tomeasure a constituent of the tissue.
 118. Apparatus for facilitating adiagnosis of a condition of a central nervous system (CNS) of a subject,comprising a stimulator adapted to: apply an electrical signal to atleast one site of the subject, the site selected from the listconsisting of: a sphenopalatine ganglion (SPG) of the subject, ananterior ethmoidal nerve of the subject, a posterior ethmoidal nerve ofthe subject, a communicating branch between an anterior ethmoidal nerveand a retro-orbital branch of an SPG of the subject, a communicatingbranch between a posterior ethmoidal nerve and a retro-orbital branch ofan SPG of the subject, a greater palatine nerve of the subject, a lesserpalatine nerve of the subject, a sphenopalatine nerve of the subject, acommunicating branch between a maxillary nerve and an SPG of thesubject, a nasopalatine nerve of the subject, a posterior nasal nerve ofthe subject, an infraorbital nerve of the subject, an otic ganglion ofthe subject, an afferent fiber going into the otic ganglion of thesubject, an efferent fiber going out of the otic ganglion of thesubject, a vidian nerve of the subject, a greater superficial petrosalnerve of the subject, and a lesser deep petrosal nerve of the subject,and configure the signal so as to cause an increase in molecular passagebetween the CNS and another body compartment of the subject, so as tofacilitate the diagnosis of the CNS condition.
 119. The apparatusaccording to claim 118, wherein the apparatus is adapted to measure aconstituent of the other body compartment.
 120. Apparatus forfacilitating a diagnosis of a condition of a central nervous system(CNS) of a subject, comprising a stimulator adapted to: apply anelectrical signal to at least one site of the subject, the site selectedfrom the list consisting of: a sphenopalatine ganglion (SPG) of thesubject, an anterior ethmoidal nerve of the subject, a posteriorethmoidal nerve of the subject, a communicating branch between ananterior ethmoidal nerve and a retro-orbital branch of an SPG of thesubject, a communicating branch between a posterior ethmoidal nerve anda retro-orbital branch of an SPG of the subject, a greater palatinenerve of the subject, a lesser palatine nerve of the subject, asphenopalatine nerve of the subject, a communicating branch between amaxillary nerve and an SPG of the subject, a nasopalatine nerve of thesubject, a posterior nasal nerve of the subject, an infraorbital nerveof the subject, an otic ganglion of the subject, an afferent fiber goinginto the otic ganglion of the subject, an efferent fiber going out ofthe otic ganglion of the subject, a vidian nerve of the subject, agreater superficial petrosal nerve of the subject, and a lesser deeppetrosal nerve of the subject, and configure the signal so as to causean increase in molecular passage between cerebrospinal fluid (CSF) ofthe subject and another body fluid of the subject, so as to facilitatethe diagnosis of the CNS condition.
 121. The apparatus according toclaim 120, wherein the apparatus is adapted to measure a constituent ofthe other body fluid.
 122. Apparatus for facilitating a diagnosis of acondition of a central nervous system (CNS) of a subject, comprising astimulator adapted to: apply an electrical signal to at least one siteof the subject, the site selected from the list consisting of: asphenopalatine ganglion (SPG) of the subject, an anterior ethmoidalnerve of the subject, a posterior ethmoidal nerve of the subject, acommunicating branch between an anterior ethmoidal nerve and aretro-orbital branch of an SPG of the subject, a communicating branchbetween a posterior ethmoidal nerve and a retro-orbital branch of an SPGof the subject, a greater palatine nerve of the subject, a lesserpalatine nerve of the subject, a sphenopalatine nerve of the subject, acommunicating branch between a maxillary nerve and an SPG of thesubject, a nasopalatine nerve of the subject, a posterior nasal nerve ofthe subject, an infraorbital nerve of the subject, an otic ganglion ofthe subject, an afferent fiber going into the otic ganglion of thesubject, an efferent fiber going out of the otic ganglion of thesubject, a vidian nerve of the subject, a greater superficial petrosalnerve of the subject, and a lesser deep petrosal nerve of the subject,and configure the signal so as to cause an increase in molecular passagebetween cerebrospinal fluid (CSF) of the subject and a tissue of thesubject, so as to facilitate the diagnosis of the CNS condition. 123.The apparatus according to claim 122, wherein the apparatus is adaptedto measure a constituent of the tissue.
 124. Apparatus for treating acondition of a central nervous system (CNS) of a subject, comprising astimulator adapted to: stimulate sphenopalatine ganglion (SPG)-relatedtissue of the subject by applying an electrical signal to theSPG-related tissue, the SPG-related tissue selected from: an SPG of thesubject and nerve fibers of the subject which are directly anatomicallyconnected to the SPG, and configure the stimulation so as to cause anincrease in clearance of a neurotoxic compound from a brain of thesubject through a blood brain barrier (BBB) of the subject to a systemicblood circulation of the subject, so as to treat the CNS condition. 125.The apparatus according to claim 124, wherein the stimulator is adaptedto directly stimulate the SPG.
 126. Apparatus for treating a conditionof a central nervous system (CNS) of a subject, comprising a stimulatoradapted to: stimulate sphenopalatine ganglion (SPG)-related tissue ofthe subject by presenting an odorant to an air passage of the subject,the SPG-related tissue selected from: an SPG of the subject and nervefibers of the subject which are directly anatomically connected to theSPG, and configure the stimulation so as to cause an increase inclearance of a neurotoxic compound from a brain of the subject through ablood brain barrier (BBB) of the subject to a systemic blood circulationof the subject, so as to treat the CNS condition.
 127. Apparatus fortreating a condition of a central nervous system (CNS) of a subject,comprising a stimulator adapted to: stimulate sphenopalatine ganglion(SPG)-related tissue of the subject by applying an electrical signal tothe SPG-related tissue, the SPG-related tissue selected from: an SPG ofthe subject and nerve fibers of the subject which are directlyanatomically connected to the SPG, and configure the stimulation so asto cause an increase in clearance of a neurotoxic compound fromcerebrospinal fluid (CSF) of the subject through a blood brain barrier(BBB) of the subject to a systemic blood circulation of the subject, soas to treat the CNS condition.
 128. The apparatus according to claim127, wherein the stimulator is adapted to directly stimulate the SPG.129. Apparatus for treating a condition of a central nervous system(CNS) of a subject, comprising a stimulator adapted to: stimulatesphenopalatine ganglion (SPG)-related tissue of the subject bypresenting an odorant to an air passage of the subject, the SPG-relatedtissue selected from: an SPG of the subject and nerve fibers of thesubject which are directly anatomically connected to the SPG, andconfigure the stimulation so as to cause an increase in clearance of aneurotoxic compound from cerebrospinal fluid (CSF) of the subjectthrough a blood brain barrier (BBB) of the subject to a systemic bloodcirculation of the subject, so as to treat the CNS condition.